Ionizing Radiation Exposure and Risk of Gastrointestinal ...€¦ · Ionizing Radiation Exposure...

Ionizing Radiation Exposure and Risk of

Gastrointestinal Cancer: A Study of the Ontario

Uranium Miners

by

Minh Tam Do

A thesis submitted in conformity with

the requirements for the degree of

Doctor of Philosophy Epidemiology (PhD)

Graduate Department of the Dalla Lana School of Public Health

The University of Toronto

© Copyright by Minh Tam Do 2009

ii

Ionizing Radiation Exposure and Risk of Gastrointestinal Cancers:

A Study of the Ontario Uranium Miners

Minh Tam Do

Doctor of Philosophy Epidemiology (PhD)

Dalla Lana School of Public Health

University of Toronto

2009

Abstract

Rationale/Objective: Excess lung cancer risks associated with exposure to

inhaled radon decay products among uranium miners has well been

established. Although ingestion is also a potentially important route of exposure,

the relationship between ingested radon decay products and gastrointestinal

cancer risks are not well examined. The objective of this study is to determine

the relationship between exposure to radon decay products and the incidence

and mortality of gastrointestinal (esophagus, stomach, and colorectal) cancer

among men employed as uranium miners in Ontario. Secondly, to determine

whether the duration of exposure (dose rate), years since last exposure and age

at first exposure modify these associations.

Methods: A cohort of miners who had ever worked in an Ontario uranium mine

between 1954 and 1996 was created using the Mining Master File and the

National Dose Registry. Cumulative radon exposures measured in Working Level

iii

Months (WLM) were previously estimated for each miner. Cancer diagnoses

(1964-2004) and cancer deaths (1954-2004) occurring in Ontario were

determined by probabilistic record linkage with the Ontario Cancer Registry. To

calculate person-years at risk, non-cancer deaths were also ascertained from

the Ontario mortality file for the period between 1954 and 2004. Poisson

regression methods for grouped data were used to estimate the relative risks

(RR) and 95% Confidence Intervals (CI) by exposure level.

Results/Conclusions: The final cohort consisted of 28,273 Ontario uranium miners.

By the end of 2004, 34 miners had been diagnosed with esophageal cancer, 86

with stomach cancer, and 359 with colorectal cancer. There were 40 deaths

due to esophageal cancer, 69 from stomach cancer, and 176 from colorectal

cancer. When comparing the highest cumulative exposure category (>40 WLM)

to the referent group (0 WLM), significant increases in both stomach (RRIncidence=

2.30, 95% CI;1.02-5.17 and RRMortality=2.90, 95% CI;1.11-7.63) and colorectal

cancers (RRIncidence =1.56, 95% CI;1.07-2.27 and RRMortality =1.74, 95% CI;1.01-2.99)

after adjusting for age at risk and period effects. However, no relationships were

observed for esophageal cancer. Suggestive evidence of modifying effects of

these associations by duration of employment (dose rate) and years since last

exposure for colorectal cancer was also observed.

iv

Acknowledgments

This thesis would not have been possible without the selfless contributions of many individuals. First and foremost, I would like to thank Loraine whom I consider to be the perfect mentor. Despite her many competing commitments, Loraine always had time to discuss new ideas and challenged me to think while keeping me on track. I would like to thank Jim for our countless discussions about exposures and biologically relevant doses. This directed me to delve into the ICRP literature, which at the time seemed quite intimidating, but in the end, enriched my knowledge of radiation dosimetry. I would also like to thank Wendy for her infectious enthusiasm of biostatistics and Jennifer for her epidemiological expertise.

My friends at Cancer Care Ontario have made this experience an enjoyable one. I am

particularly indebted to Yen for her constant ‘gentle reminders’ of upcoming deadlines and to Nelson for his amazing ability for remembering minute details of cancer registration and for his expertise in record linkage. Who would have thought that a friendship could develop from geek talk about data?

This thesis has benefited from a number of experts in this specialized area of radiation

epidemiology, all of whom I have pestered over the years. Specifically, I would like to thank Willem Sont at the National Dose Registry, Bob Kusiak formerly of the Ontario Ministry of Labour, and Doug Chambers at Senes for their knowledge and insight. I would also like to thank Paul Villeneuve for his willingness to share his knowledge and for his technical assistance.

I would like to thank all my examiners, Drs Andrea Sass-Kortsak, Paul Corey, Cameron

Mustard, and Kristan Aronson for taking time from their busy schedules and for providing invaluable suggestions, enhancing the thesis and subsequent manuscripts. In particular, I would like to thank Dr. Aronson who drove from Kingston in order to be present for my defence.

I would also like to acknowledge the financial assistance provided to me over the years through my work with the Occupational Cancer Research and Surveillance Pilot project at Cancer Care Ontario and stipends received from the Programme of Research in the Environmental Etiology of Cancer (PREECAN) and a research grant jointly provided by the Canadian Institutes for Health Research (CIHR Grant # MOP-77725) and Workplace Safety Insurance Board of Ontario (WSIB Grant #05034).

Finally, I would like to thank my parents (Van and Thuy) for their constant encouragement who kept asking: Are you done yet? What’s taking you so long? On a more serious note, I am forever indebted to my partner and lifelong friend Doreen, who had the misfortune of sharing this journey with me. Thank You for your patience and understanding! Finally, I would like to thank Yuliah, my Little Girl, for providing the ultimate inspiration and incentive for finishing this thesis. Little Girl, Daddy is done!

Minh

June 15th, 2009

v

Thesis Table of Contents

Chapter 1: Objectives and review of the literature..…………………………..……… 1

Chapter 2: Research methodology ……………………………………….….………… 45

Chapter 3: Assessment of the loss to follow-up ……………………………………… 85

Chapter 4: Gastrointestinal cancer risks associated with exposure to radon decay

products ……………………………….……………..…………………….. 117

Chapter 5: Summary discussions and conclusions ……..…………………………... 191

Appendices ……………………………………………………………….…………… 207

vi

Chapter 1 Table of Contents

Abstract..................................................................................................................................................... ii

Acknowledgments .............................................................................................................................. iv

Description of thesis ............................................................................................................................vii

Statement of Author Contributions.............................................................................................. ix

Statement of Contributions from Others .................................................................................... x

Abbreviation .......................................................................................................................................... xi

Chapter 1: Objectives and Review of the Literature

Introduction ............................................................................................................................................. 2

Objectives ................................................................................................................................................ 4

Gastrointestinal Cancers: Esophagus, Stomach, and Colorectal .................................. 5

Justification for Selected Cancers ..............................................................................5

Gastrointestinal Cancer Incidence and Mortality ...................................................6

Ionizing Radiation ............................................................................................................................... 16

Sources of Ionizing Radiation Exposure....................................................................16

Occupational Exposures to Ionizing Radiation...................................................17

Radon Decay Products ..............................................................................................18

Carcinogenic Effects of Ionizing Radiation .............................................................20

Carcinogenic Potential of the Gastrointestinal Tract ............................................22

Factors Influencing Carcinogenic Risks of Radon Decay Products ....................24

Duration of exposure...............................................................................................24

Years Since Last Exposure.......................................................................................25

Age at Exposure ......................................................................................................26

Gastrointestinal Cancer Risks of Radon Decay Products .....................................26

Uranium Mining in Ontario......................................................................................30

Cancer Risks at Low Doses.....................................................................................31

Summary of Review ........................................................................................................................... 33

Scientific and Practical Relevance of this Research.......................................................... 33

Chapter 1 References ...................................................................................................................... 35

vii

Description of thesis

This thesis is organized into 5 chapters. The content of each chapter is as follows:

Chapter 1 sets the context of this research by synthesizing the literature and

identifying the knowledge gaps regarding the cancer effects of

exposure to ionizing radiation on the development of and death

from esophageal, stomach, and colorectal cancers. This chapter

also contains the objectives that this work addresses.

Chapter 2 contains the methodology used in this thesis. Specifically, it

contains detailed descriptions of the databases used to create the

cohort and assemble exposure information, record linkage

procedures used to determine cancer status of the cohort

members, persons-years estimation, and the statistical methods

used to derive risk estimates associated with exposure to radon

decay products.

Chapters 3 and 4 contain the main results of this study. Since the cohort was

linked to the provincial (Ontario) rather than national database,

Chapter 3 focuses on the impact of the loss to follow-up of miners

who emigrated from Ontario and whose diagnosis and deaths

status could not be determined as a result. Chapter 4 presents the

results for cancer risks estimates associated with exposure to

viii

cumulative exposure to low levels of alpha radiation emitted from

radon decay products.

Chapter 5: Given the state of knowledge and issues raised in chapter 1 and

the findings in chapters 3 and 4 the relevance of this study, its

strengths, limitations, and recommendations for future work in this

area are discussed in this Chapter.

ix

Statement of Author Contributions

The author played a substantial role in all aspects of this study, including its

conceptualization, protocol development, data acquisition from three data

custodians as needed, ethics approval from Health Canada and the University

of Toronto, analysis, writing of the thesis and presentation of study findings.

Methods and preliminary results from this work have been presented at the

following venues:

1. University of Toronto, Public Health Sciences Research Day, Toronto,

Ontario. (Poster, February 2006);

2. Canadian Society for Epidemiology and Biostatistics 3rd National Student

Conference Calgary, Alberta. (Oral, May 2007);

3. 19th International Conference on Epidemiology in Occupational Health

(EPICOH 2007), Banff, Alberta. (Oral, October 2007);

4. Centre for Research in Environmental Epidemiology (CREAL), Barcelona,

Spain (Post-doctoral interview with Dr. Elisabeth Cardis, July 2008).

5. Canadian Society for Epidemiology and Biostatistics 4th National Student

Conference Ottawa, Ontario. (Oral, May 2009); and,

6. Canadian Society for Epidemiology and Biostatistics (CSEB) and

Association of Public Health Epidemiologists in Ontario (APHEO) Joint

Conference Ottawa, Ontario. (Oral, May 2009).

x

Statement of Contributions from Others

This research is a sub-component of a larger funded study where Dr.

Loraine Marrett is the principal investigator and Drs. Jennifer Payne and John

McLaughlin the co-investigators. Continuous assistance was obtained from all

committee members. Specifically, Dr. Marrett provided the overall guidance on

this study; Dr. Payne provided additional epidemiological support, while

statistical expertise and exposure assessment were sought from Drs. Wendy Lou

and James Purdham. Nelson Chong (Research Associate, Cancer Care Ontario)

conducted the record linkages and provided technical assistance on the SAS

programming as needed. External expert advice was also sought from Dr.

Willem Sont (National Dose Registry of Health Canada), Mr. Robert Kusiak

(formerly of the Ontario Ministry of Labour), Dr. Doug Chambers (SENES

Consultants Ltd), and Dr. Paul Villeneuve (Health Canada) regarding exposure

assessment and analysis.

xi

Abbreviation

ASIR/ASMR Age Standardized Incidence/Mortality Rate

CCO Cancer Care Ontario

CI Confidence Interval

ERR Excess Relative Risk

GI Gastrointestinal

IR Ionizing Radiation

ICD-9 International Classification of Diseases, 9th Revision

ICRP International Commission on Radiological Protection

LNT Linear no-threshold

OUMC Ontario Uranium Miners Cohort

u/mSv Micro/Milli-Sievert

MMF Mining Master File

MSF Master Study File

NDR National Dose Registry

LET Linear Energy Transfer

OCR Ontario Cancer Registry

OMD Ontario Mortality Database

OUMC Ontario Uranium Miners Cohort

ppm Parts per million

RD Radon Daughters or Radon Progeny

RR Relative Risk

U3O8 Uranium oxide

WHF Work History File

WL/M Working Level/Month

1

Chapter 1: Objectives and Review of the Literature

2

Introduction

Despite the extensive literature supporting a consistent link between

exposure to inhaled high energy alpha particles emitted from radon and its

decay products and associated increased risk of lung cancer mortality among

uranium miners [1, 5-22], there remain major knowledge gaps. The first pertains

to whether the same human carcinogenicity responsible for increased lung

cancer mortality is true as well for non-lung cancer sites, particularly for major

organs that come into direct contact with radon decay products through

ingestion. Secondly, cancer risks to date have focused primarily on mortality as

an endpoint. While this is appropriate for cancers with high fatality rates such as

lung cancer, incidence is arguably a better measure of the full impact of the

health risks associated with exposure to ionizing radiation for cancers with

relatively good survival, such as those of the colon and rectum [5]. Finally, the

renewed debate on the scientific uncertainty regarding cancer risks at low

doses requires closer examination [6, 7]. Cancer risks associated with exposure

to gamma radiation for uranium miners remain a challenge and will not be

addressed in this thesis due to lack of data on gamma exposure.

The Ontario Uranium Miners (OUM) cohort is a large cohort of men

employed to mine uranium ore in Ontario beginning in 1954. Compared to other

uranium mines elsewhere, all Ontario uranium mines were of low ore grade,

approximately 0.15% uranium oxide (U3O8) or less. Because of the low uranium

ore grade, the men employed within these mines to extract uranium oxide were

3

typically exposed to relatively lower dose rates of ionizing radiation relative to

mines operated elsewhere. Despite the low dose rate, excess in lung cancer

mortality has been well demonstrated for this cohort [8-10]. Like other cohorts,

cancer risks for non-lung cancer effects remain inconclusive. The large Ontario

Uranium Miners cohort, combined with the long follow-up, provides a unique

opportunity to address research questions regarding the potential adverse long-

term health impacts of exposures to relatively low levels of ionizing radiation, in

particular, as it relates to cancer effects on major organs along the digestive

tract where the research is still lacking.

4

Objectives

The overall aim of this study is to assess the risk of gastrointestinal cancer

amongst male workers employed in Ontario uranium mines between 1954 and

1996 and who were followed until the end of 2004. Within this cohort, the

specific objectives of this study are as follows:

1. To determine whether the risk of diagnosis (incidence) of or death

(mortality) from gastrointestinal cancers (esophageal, stomach,

and colorectal) is associated with cumulative exposures to radon

decay products; and,

2. To determine whether the duration of exposure (dose rate), years

since last exposure, and age at first exposure modify these

associations.

5

Gastrointestinal Cancers: Esophagus, Stomach, and Colorectal

Justification for Selected Cancers

Three sites within the gastrointestinal tract are targeted in this thesis; the

esophagus, stomach, and colon-rectum. These three major sites along the

digestive tract were of particular interest given the plausible hypothesis that

direct contact through ingestion of radon decay products, a known human

carcinogen [2], provides the basis for the initiation of the carcinogenic process.

In the past, mining was much less automated compared to mining

practices of today. Men worked in a harsh physical environment performing

physically demanding tasks as part of their daily work requirements. High levels

of physical exertion in dusty environments provided the medium for inhaled dust

particles laden with radon decay products to initially be trapped by the mucus

lining of the bronchial wall and lining of the chest cavity and later transported

back to the throat by mucociliary action [11]. The mucus, containing dust,

dissolved radon and its radon decay products, would invariably then be

swallowed, thus ending up in the digestive tract.

In addition to the many working hours spent underground, breaks

(including eating) were taken within the ore body [12]. As such, airborne dust

containing radon and its decay products from the mine environment would not

only be inhaled, but ingested as well. Ingestion of contaminated food or water

6

provides a direct pathway to the esophagus, stomach and other internal organs

within the digestive tract.

For ingested radon decay products, it has been shown that the burden of

the ingested radiation dose would be to the stomach [13] (Table1). In a

simulation study, Kendall and Smith showed that for an estimated annual

ingestion of water containing 1000 Bq per liter of water, an equivalent dose of 50

mSv would be directed to the stomach as compared to only 1.26 mSv directed

to the lungs [13].

Table 1: Estimated annual doses of ingested radon (222Rn) in water containing

1000 Bq per liter of water.

Organ Annual dose at 1000 Bq/L

water (mSv)

Stomach 50.40

Small intestine 2.60

Colon 0.10

Lung 1.26 Source: Kendall and Smith (2002) [13] dose to the

esophagus not evaluated.

Gastrointestinal Cancer Incidence and Mortality

For a small proportion of individuals, cancer can develop at different parts

along the gastrointestinal (GI, Figure 1) tract. In Ontario, it is estimated that

cancers of the GI for the 3 main organs (esophagus, stomach, and colorectal)

collectively accounted for 17% (n=5450) of all new cancer cases and 19%

(n=2710) of all cancer mortalities in 2008 among Ontario men [14]. However, the

7

epidemiology of these cancers differs in terms of trends, risk factors, and survival.

The following sections describe the epidemiology of these cancer sites in detail.

Figure 1: Schematic of gastrointestinal cancers of interest (ICD-9 coding) in this

study.

(Note: Diagram adapted from the American Cancer Society with permission for reproduction in

this thesis [15])

8

Cancer of the Esophagus (ICD-9: 150)

In 2008, it is expected that 450 men in Ontario will be diagnosed with

esophageal cancer. The age standardized incidence rate for esophageal

cancer is 6 per 100,000 [14] representing the 14th most common cancer

diagnosed among Ontario men. Although esophageal cancer occurs less

frequently than many other cancers, it is highly fatal since most patients with

esophageal cancer present at advanced stages of the disease [16]. According

to the Canadian Cancer Society and the National Cancer Institute of Canada,

only 14% of esophageal cancer patients are likely to be alive 5 years after

diagnosis [14]. Figure 2 (left panel) shows 3-year moving averages of age-

standardized incidence and mortality rates from 1964 to 2004 for Ontario men.

For this period, both incidence and mortality rate trends are fairly stable and the

ratios of incidence to mortality are almost at unity.

Among morphologically verified esophageal cancer cases, squamous

cell and adenocarcinoma morphologies account for 95 percent of cases

worldwide [16, 17]. Squamous cell carcinoma arises from the stratified squamous

epithelial lining of the esophagus while the adenocarcinomas develop from

columnar glandular cells that replace the squamous epithelium [18]. In Ontario,

approximately two-thirds of esophageal cancer cases are squamous cell

carcinomas, with the remainder being mainly adenocarcinomas [17]. Over the

past 10 years, however, the incidence of adenocarcinoma is increasing while

9

that for squamous cell carcinoma is on the decrease [16, 18, 19]. The reasons for

these trends are unknown.

The risk of developing esophageal cancer increases with age and is rarely

diagnosed in individuals under 40 years of age [15]. Smoking can also lead to

increased risk of developing esophageal cancer[15]. The impact of diet and

physical activity was recently reviewed by the World Cancer Research Fund

and the American Institute for Cancer Research[20]. To date, there is convincing

evidence that alcohol consumption can increase the risk of esophageal cancer

while intake of non-starchy vegetables, fruits, and food with high content of

beta-carotene and vitamin C can decrease the risk of developing cancer of

the esophagus [20] (Table 2).

Men are 3 times more likely to be diagnosed with esophageal cancer

[15]. It is possible that some of the increases in diagnosis of esophageal cancer

among men are associated with occupational related factors. In the past, men

were employed more frequently in industrial processes than women. In Ontario,

most of the miners employed in the mining industry were men. Cancer of the

esophagus has been associated with exposure to ionizing radiation in some

studies, especially for squamous cell carcinomas [18, 21].

The latent period between esophageal cancer initiations to diagnosis is

unknown. Estimates of this time window are quite variable given the small

sample size of studies conducted to date. It has been estimated that

10

progression from Barrett’s Esophagus to high grade dysplasia to

adenocarcinoma is approximately from 12 to 17 years [22].

Cancer of the Stomach (ICD-9: 151)

According to the World Health Organization, stomach cancer is the

second leading cause of cancer mortality worldwide [23]. However, incidence

and mortality rates vary tremendously throughout the world. The highest

incidence can be observed in Asia, particularly in Japan, while lower incidence

rates can be observed in Canada, the United States and other Western societies

[24]. In Ontario, approximately 700 men are expected to be diagnosed with

stomach cancer in 2008 [14]. Stomach cancer is the 10th most common cancer

diagnosed among Ontario men. Incidence and mortality have been declining

for many years (Figure 2, left Graph).

A number of dietary factors can influence the risk profile of stomach

cancer. A declining incidence and mortality trends are likely attributed to

increased consumption of fresh foods including preservative-free meats and fish,

likely influenced by availability of refrigeration [25]. High content of nitrates and

related compounds in foods has also been associated with increased risk of

stomach cancer (Table 2)[20], as well as smoking and excess alcohol

consumption [26].

Almost all morphologically verified diagnosed stomach cancers are of

the adenocarcinoma type [27]. Like esophageal cancer, the risk of developing

stomach cancer increases with age [15]. Infection with Helicobacter pylori has

11

been shown to cause acute gastric inflammation, increasing the risk of gastric

cancer [26].

The incidence of stomach cancer is much higher among men. In Ontario,

the age-standardized incidence rate for stomach cancer in men is 10 while only

5 per 100,000 for women per year [14]. Occupational factors have been

associated with increased risk of stomach cancer. Kusiak and colleagues

showed that gold mining was associated with an increase in stomach cancer

risk (SMR=1.52, 95%CI 1.25-1.85) [28]. Exposure to arsenic, chromium, diesel

emissions, and aluminum powder were implicated as possible explanations for

these miners [28]. There is some evidence that painters and individuals

employed in the rubber industry have an increased risk of stomach cancer [29].

Internal exposure to ingested radon decay products has also been implicated

for stomach cancer risk. Darby and colleagues pooled data from 11 cohorts of

uranium miners and compared it to a standard population, their analysis

showed a 33% excess risk of stomach cancer (SMR=1.33, 95% CI 1.16-1.52) [30].

Cancer of the colon and rectum (ICD-9: 153-154, 159.0)

Colorectal cancer is the second leading cause of cancer death in

Ontario. One in 14 men is expected to develop colorectal cancer during their

lifetime and one in 27 will die of it [14]. Beginning in 1968, the incidence of

colorectal cancer among men increased sharply (Figure 2, right), but appeared

to plateau by 1988. Approximately half of all colorectal cancers diagnosed

result in death. The age-standardized mortality rate peaked in 1988 at 35 deaths

12

per 100,000 in Ontario. Despite the significant burden of this disease, the causes

of colorectal cancer remain unknown. Like esophageal and stomach cancer,

colorectal cancer incidence is associated with increased age and is higher

among males than females [31].

Etiologic studies have revealed that diet can modify the risk of developing

colorectal cancer. Most common dietary factors examined include intake of

fats, fiber, fruits and vegetables. Results to date suggest that a high intake of red

meat, processed meat and alcohol increase the risk of developing colorectal

cancer. Conversely, a diet rich in foods with high dietary fiber, garlic, milk, and

calcium contributes to a decreased risk of colorectal cancer[20] (Table 2). The

risk of developing colorectal cancer has also been shown to be inversely

associated with physical activity [22].

Like the other cancers, the time window between colorectal cancer initiation to diagnosis

is unknown but it has been suggested that it can to take several decades given that initiation to

adenoma can take 5 to 20 years and adenoma to cancer another 7 to 8 years [22].

13

Table 2: Summary of risk of developing cancer of the esophagus, stomach, or colorectal cancers associated

with foods, nutrition, and level of physical activity.

Esophageal Stomach Colorectal Level of Evidence Decreased Risk Increased Risk Decreased Risk Increased Risk Decreased Risk Increased Risk

Convincing None identified Alcoholic Drinks Body Fatness

None identified None identified Physical Activity Red meat Processed meat Alcoholic drinks Body fatness Abdominal fatness Adult attained height

Probable Non-starchy foods Fruits Foods containing beta-carotene or Vitamin C

Mate (South Am. Drink)

Non-starchy vegetables Allium vegetables Fruits

Salt Salted and salty foods

Foods containing dietary fiber, garlic, milk, calcium

Limited - suggestive

Foods containing dietary fiber, folate, pyridoxine, vitamin E

Red meat Processed meat High temperature drinks

Pulses (legumes) Foods containing selenium

Chili Processed meat Smoked foods Grilled animal foods

Non-starchy foods Fruits Foods containing folate, selenium, Vitamin D Fish

Foods containing iron Cheese Foods containing animal fat or sugars

Source: World Cancer Research Fund and the American Institute for Cancer Research [20]

14

Figure 2: Three-year moving average of age-standardized incidence and mortality rate for cancer of the

esophagus and stomach (left) and colorectal (right) of Ontario men, 1964-2004

Source: SEERSTAT (Ontario) data generated 31 May 2008 [3]

0

10

20

30

40

50

60

70

19641968

19721976

19801984

19881992

19962000

2004

Ag

e-S

tan

dar

diz

ed R

ate

(per

100

,000

)

Colorectal Cancer (Incidence)

Colorectal Cancer (Mortality)

0

5

10

15

20

25

30

1964

1968

1972

1976

1980

1984

1988

1992

1996

2000

2004

Year of Diagnosis/Death

Ag

e-S

tan

dar

diz

ed R

ate

(per

100

,000

)

Esophageal Cancer (Incidence)

Esophageal Cancer (Mortality)

Stomach Cancer (Incidence)

Stomach Cancer (Mortality)

15

Table 3: Summary of descriptive epidemiology and risk factors associated with gastrointestinal cancers.

Descriptive Epidemiology Associated Risk Factors

Gastrointestinal Cancer Site

(ICD-9) ASIR (per

10^5)*

ASMR (per

10^5)*

5-Yr Relative Survival Ratio

(95% CI)**

Oc

cu

pa

tio

-

na

l

fac

tors

***

Sm

okin

g

Die

t

(Hig

h fib

er)

Mic

ro-

org

an

ism

Ag

e

Se

x

(ma

les)

Esophagus (150) 6 7 14 (13-16) ■ ▲ ▼ ■ ▲ ▲

Stomach (151) 10 6 22 (21-24) ■ ▲ ■ ▲ ▲ ▲

Colorectal (153, 154, 159.0) 60 25 62 (61-63) ■ ▲ ▼ ■ ▲ ▲

Note: *ASIR/ASMR - Age-standardized incidence/mortality rate, standardized to 1991 Canadian population, Ontario men; **Survival of Canadian men during follow-up 2001-03, excluding Quebec [14] ; ▲- Increased risk; ▼-

Decreased risk; ■- Inconclusive; *** Siemiatycki et al (2004) [29] suggestive occupations associated with stomach

cancer (Painters and rubber industry), substance or mixture suggestive associated with esophageal cancer (Soots;

tetrachloroethylene), none mentioned for esophageal cancer.

16

Ionizing Radiation

Naturally occurring uranium consists mainly of 3 different isotopes (238U,

235U, and 234U), all of which are unstable and readily break down in order to form

more stable elements. In the process of breaking down, uranium isotopes emit

ionizing radiation (IR) which are subatomic particles (alpha particles) or

electromagnetic waves that are capable of extracting electrons from atoms

and molecules as it passes through cells or tissues of living organisms [32]. The

International Agency for Research on Cancer (IARC) considers IR to be a human

carcinogen [33].

Sources of Ionizing Radiation Exposure

Naturally occurring radioactive materials are common in the

environment, and as such, all humans are exposed to some level of ionizing

radiation on a daily basis [34]. Sources of these exposures include cosmic

radiation, rocks, soil, building materials and even some foods [34]. Collectively,

the ionizing radiation from these and similar sources is referred to as background

radiation. It has been estimated that natural background radiation accounts for

approximately 82% of the general population’s total exposure [34]. The

remaining 18% is from human activities, including medical and occupational

related exposures [34].

17

Occupational Exposures to Ionizing Radiation

In Canada, occupational exposure to ionizing radiation (IR) is monitored

by the National Dose Registry (NDR). To date, the NDR contains data for over

500,000 workers with exposures to IR. These workers are typically employed in the

area of industry, research, medicine, nuclear power, and mining. Uranium

miners are among the workers monitored by the NDR. Most radiation exposures

are measured using personal dosimeters provided by the National Dosimeter

Services [35], however, because of harsh working conditions, uranium miners did

not wear dosimeters until the early 1980s when a dosimeter specially designed

for capturing radiation in the dusty mining environment was developed [35].

Among the various occupations susceptible to radiation exposure, miners

are among the highest. Figure 3 shows the relative annual effective dose

endured by workers employed in occupations susceptible to exposure to high

levels of ionizing radiation. On average, the mining occupation experiences 4.4

mSv of ionizing radiation per year. In relative terms, uranium miners, on average,

receives almost twice the level of exposure of nuclear reactor operators and

almost ten times the level of individuals working in the medical field (See Figure

3).

18

Figure 3: Average annual effective dose per monitored worker in different

occupations.

Radon Decay Products

A summary of the uranium decay chain is shown in Figure 4. Uranium-238

(238U) is by far the most abundant of the three uranium isotopes. Uranium-238 has

a half-life of approximately 4.4 billion years. Uranium-238 breaks down to

radium-226 (226Ra) then decays to radon gas (222Rn). Radon gas (222Rn) is a

noble (inert) gas with a half-life of 3.8 days [36]. It, in turn, breaks down into a

series of four short-lived decay products commonly known as ‘progeny’ or

‘radon decay products’ (RDP). The four radon decay products are polonium-

218 (218Po), lead-214 (214Pb), bismuth-214 (214Bi), and polonium-214 (214Po). The

Sources: Collated from IARC [2] and UNSCEAR [4].

4.4

2.5

0.8

0.8

0.7

0.5

0 1 2 3 4 5

Mining

Reactor operation

Fuel fabrication

Research

Military activities

Medical applications

milli-Sieverts (mSv)

Occ

upat

ion

19

combined half-life of these four radon decay products is approximately 51

minutes (Figure 4). Both polonium-218 and polonium-214 emit high energy

alpha particles as they decay [36]. Alpha particles are high-energy helium

nuclei whose energy is dissipated by transferring to host cells as they come into

contact. This ‘transfer’ of energy can cause atoms of the host cells to ionize,

leading to cellular damage. This decay chain continues until stable lead (206Pb)

is formed.

The activity of a radionuclide is determined by the rate of radioactive

decay, and it can be measured by the number of disintegrations per minute.

However, in uranium mines, it is not practical to measure individual

radionuclides; instead, the concept of working levels (WL) was developed and

used to measure the concentration of the short lived radon decay products.

Working Level measures the potential alpha energy concentration of the four

short lived radon decay products in air. One WL is defined as any combination

of radon decay products per liter of air that will result in the emission of 1.3x106

million electrons. The total dose of radon decay products is commonly

expressed in working level months (WLM) where 1 WLM is equal to the inhalation

of air concentration of 1 WL for a period of 170 hours, the approximate number

of hours worked in one month [37].

In the mining environment, radon gas and its decay products can exist in

the air as ions or attached to dust particles. As such, within the mine, the level of

ionizing radiation can be controlled by ventilation conditions of the mine where

20

increasing ventilation can drastically reduce the concentration of radon and its

decay products concentration. In fact, stricter regulatory controls implemented

in the late 1960s resulted in a dramatic decrease in the radon concentrations in

Ontario mines [38].

Carcinogenic Effects of Ionizing Radiation

Damage to cellular DNA is thought to be the initiating event leading to

the development of ionizing radiation-induced cancers. This damage, which

has been well documented in both in vivo and in vitro systems [39] includes

chromosome aberrations, reciprocal translocations, sister chromatid exchange,

DNA fragmentation in mice and other mammalian cells [40]. The mechanism of

damage occurs by both direct and indirect interactions of the ionizing particles

with the DNA double helix [39]. In direct interaction, ionizing particles can collide

with the DNA strands breaking the bonds responsible for maintaining the DNA

structure [39]. Indirect interaction can react with water to generate reactive

radicals which can subsequently break DNA bonds [39]. While cells are capable

of self-DNA repair, repeated damage to DNA strands can result in mutations

and lead to uncontrolled cell growth [41].

21

Figure 4: Simplified uranium decay chain of uranium (238-U) to radon gas (222-

Rn) and short-lived radon decay products.

Uranium

(238-U)

Radium

(226-Ra)

Radon

(222-Rn)

Radon

Daughter 1

= “Radon and its

decay products”

Working Level = Measure of Potential alpha

energy concentration from short lived radon

daughters/progeny

Radon

Daughter 2

Radon

Daughter 3

Radon

Daughter 4

Half-life = 4.4 billion years

Half-life = 1,620 years

Half-life = 3.8 days

Lead

(206-Pb)

Total half-life = 51 minutes

Radon

Gas

Radon

Daughters

22

Chromosomal aberrations have been examined by Smerhovsky and

colleagues in a cohort of radon-exposed miners located in the Czech Republic

[42]. The authors found a significant correlation between chromatid breaks and

radon exposure. [42] Furthermore, Meszaros and colleagues using blood

samples found that the frequency of aberrations for current and past uranium

miners was 2-3 times higher than that of the unexposed population [43]. Among

former uranium miners, the deletions were maintained well after mining had

ended [43].

Carcinogenic Potential of the Gastrointestinal Tract

Ingestion has been recognized as an important route of internal exposure

among workers exposed to harmful alpha emitters. As such the International

Commission for Radiological Protection (ICRP) developed a physiologically-

based GI Tract biokinetic model for describing transit times of ingested material

and weighting factors for various radio-sensitivity organs and tissues. The GI Tract

Model was first developed in the late 1970s [44] and updated in 2006 [45]. This

model is used by dosimetrists world-wide to estimate internal doses of ingested

radionuclides to different organs along the GI tract. The model was recently

updated to include new data on food transport, absorption, retention, and

secretion of nuclides [45].

According to the updated GI Tract Model (Table 4), transition time from

ingestion to excretion is approximately 41 hours. Less than one minute is spent in

23

the oral cavity and the esophagus combined. Three percent of the transition

time (approximately 1 hour) is spent in the stomach while 87 percent of the

transition time is spent traversing the colon. Within the uranium mining

environment, the most important alpha emitters are radon and its decay

products. Although radon gas has a half-life of 3.8 days, its decay products

have very short total half-lives of only 51 minutes (Figure 4). As such, the decay

products can deliver significant radiobiologic damage over a very short period

of time. Based on the GI Tract Model, more than half of the radiologic dose (first

half-life) from ingested radon decay products is expected to be delivered to the

stomach alone, while the colon receives only approximately 3% of the total

dose (Table 6).

Table 4: Transit times for ingested food along the gastrointestinal tract for human

males according to the gastrointestinal tract model.

Organ Transit Times

Mouth 12 Seconds

Esophagus 7 to 40 Seconds

Stomach 70 Minutes

Small Intestine 4 hours

Right Colon 12 hours

Left Colon 12 hours

Recto Sigmoid 12 hours

Source: The International Commission for Radiological

Protection (ICRP) [45].

24

Factors Influencing Carcinogenic Risks of Radon Decay Products

The main source of data for deriving cancer risks associated with exposure

to alpha radiation has been from epidemiological studies of uranium miners. In

total, there are 13 cohorts of uranium miners world wide. Of these, three are

located in Canada (Newfoundland, Ontario, and Saskatchewan). Historically,

uranium miners have been exposed to alpha radiation. Accordingly, these

exposures translate to high rates of lung cancer deaths. Excess lung cancer

mortality due to exposure to radon and its decay products have been well

documented [46-49].

In addition to the abundance of literature describing lung cancer risks

associated with exposure to radon decay products, studies have also been

conducted to examine modifiers of this dose-response relationship. Among the

most important of these are duration of exposure (dose rate), age at exposure,

and year since last exposure [47-49].

Duration of exposure

Most studies to date estimating cancer risks associated with exposure to

radon decay products have examined cumulative dose as the risk function. As

Hornung and others [47, 48] have noted, implicit in this examination is the

assumption that exposure to high levels of radon decay products over a short

period is etiologically equivalent to the same cumulative exposure over a longer

period of time. However, it has been shown that a protracted dose of low alpha

25

radiation doses delivered continuously over a relatively long period has a more

potent carcinogenic effect than the same dose delivered over a short period of

time[48]. Biological hypotheses for this observation suggest that cells are more

vulnerable to mutations during replication and that protracted doses increase

the likelihood that alpha energy released from radon decay directly affects

genetic material during mitosis [47]. This inverse dose rate has been shown in

animal studies as well as human studies, namely those examining lung cancer

risks among uranium miners [50-53]. The inverse dose rate, however, has not

been shown for gastrointestinal cancers.

Years Since Last Exposure

Since most uranium miners worked for a very short period of time, most of

the person years of follow-up are ‘inactive years’ where no additional exposures

to mining related radon occurred [47]. Several studies have found that as the

number of inactive years increases, the risk of developing cancer, if any

approaches background rates [47]. This inverse relationship has been well

documented for radon effects on lung cancer mortality for most uranium miner

cohorts [48]. The Committee on the Biological Effects of Ionizing Radiation [36]

has examined this issue and based on the pooled analysis of several miner

cohorts, it was concluded that the risk of lung cancer death associated with

exposure to radon decay products remained elevated for approximately 25

years after last exposure, after which, the risk remained constant for lung cancer

mortality. This inverse relationship has not been examined for GI cancers. With

26

the extended follow up of the Ontario cohort, it is possible to determine whether

years since last exposure would modify the dose-response relationship.

Age at Exposure

The relationship between the risk of developing disease and the age at

which exposure occurs has been a topic of much interest in radiation

epidemiology. It has been shown in mice that for some cancers, the most

susceptible age for neoplasm induction was from the neonatal through juvenile

period [54]. Data from the Life Span Studies of Japanese atomic bomb survivors

have shown that exposure to ionizing radiation in infancy and childhood is more

effective in inducing disease [55]. Similarly, susceptibility to thyroid cancer

appears to be higher in childhood and adolescent exposures than adulthood

[55].

The relationship between the risk of cancer and age at exposure to radon

decay products has not been consistently demonstrated across different

cohorts of uranium miners. For lung cancer, some studies have observed

increased cancer risks at younger age [56], while others did not observe any

associations [57]. The modifying effects of age at exposure for GI cancer are

not known.

Gastrointestinal Cancer Risks of Radon Decay Products

Cancer risks associated with exposure to ionizing radiation have been a

topic of regular review by several international agencies. These reviews were

27

mainly based on data collected from atomic-bomb survivors, uranium miners,

and other occupational cohorts such as nuclear workers where exposure is

higher than background [32, 36, 45].For health effects associated with exposure

to radon and its decay products, data from cohorts of uranium miners have

been the primary source used to evaluate cancer risks [36]. In fact, it has been

estimated that approximately 40% of lung cancer deaths among miners are

likely due to radon progeny exposure [36]. However, due to the long latency of

some solid tumors and lack of statistical power, the effects of exposure in terms

of other types of cancers is not well characterized. To date, knowledge

regarding the association between exposure to radon and gastrointestinal

cancer is limited. Only a few studies have examined this relationship and results

have been inconclusive [24, 34, 49, 58].

Darby and colleagues pooled data from 11 cohorts of miners that were

exposed to ionizing radiation to examine cancer mortality risks other than lung

cancer [30]. Of the 11 cohorts, 4 were from Canada and accounted for almost

50% of the men in the study (30,195 of the 64,209 men in the study). The Ontario

uranium miners’ cohort was the largest cohort included in this study followed by

China and Beaverlodge in Saskatchewan. Although the study observed

significant elevated risks for mortality due to stomach cancer (SMR=1.33, 95% CI;

1.16-1.52), the authors cautioned that these risks might not be due to radon

exposure since the increase was not proportional to their estimates of

cumulative exposure of ionizing radiation.

28

There were limitations with the Darby study. Firstly, not all miners had

worked in uranium mines [30]. For example, a cohort from Sweden worked in an

iron mine [30, 59], and those from China and Southwest England were tin miners.

It was not clear whether ionizing radiation from iron and tin mines were

measured in the same way as that in uranium mines or whether the methods of

mining iron/tin are similar to that of uranium. More importantly, a re-assessment

of the exposure information from one of the cohorts included in the Darby study

(Beaverlodge, Saskatchewan) demonstrated that exposure to ionizing radiation

had been substantially underestimated [60]. In a case-control study, Howe and

Stager re-estimated exposure for the Beaverlodge cohort by re-reviewing

employment records with respect to the location within the mine worked (e.g.,

stopings, drifting/raising, travel ways, and shaft areas) and using mine area-

specific exposure measurements. The revised cumulative exposure translated

into an increase of 20% in the magnitude of the risk estimate [60]. The change in

risk estimate was attributed to the reduction in random measurement error that

had biased estimates to the null [60].

Morrison and colleagues examined the mortality experience of a cohort

of 1,772 Newfoundland underground fluorspar miners with high exposure to

radon progeny [61] .For stomach cancer, they were expecting 16 fatal cases

based on Newfoundland mortality rates but observed 22 deaths (SMR = 1.35,

95% CI; 0.85-2.05) [61]. For death due to cancer of the large intestine (n=5) and

rectum (n=1) observed deaths were lower than expected but not statistically

29

significantly. However, these findings might be due to random variation due to

the small number of cases. This cohort was updated in 2005 and stomach

cancer risk remained elevated, but was not statistically significant [62].

Tomasek and colleagues examined the mortality experience of 4320 West

Bohemian (Czech Republic) underground uranium miners [63]. They observed

significantly higher than expected deaths for all types of cancers combined.

However, for esophageal (SMR = 1.22, 95% CI; 0.49-2.52), stomach (SMR = 1.05,

95% CI; 0.79-1.35), and rectal cancer (SMR = 1.04, 95% CI; 0.67-1.55), the ratio of

observed to expected exceeded 1, but was not statistically significant [63].

Laurier and colleagues examined the mortality experience of a cohort of

1785 French underground uranium miners [64]. They compared mortality

experience of cohort members employed for at least 2 years to that of the

general public. Overall, they observed 234 cancer deaths, but had only

expected 183 deaths due to cancer of all types (SMR = 1.3, 95% CI; 1.1-1.5). For

cause-specific cancer deaths, lower than expected deaths were observed for

esophagus cancer (SMR = 0.7, 95% CI; 0.4-1.4), while the number of deaths was

higher than expected for stomach (SMR = 1.1, 95% CI; 0.5-2.0) and colorectal

cancer (SMR = 1.4, 95% CI; 0.8-2.1), although no results is statistically significant

[64].

All of these studies suggested an increase in stomach cancer risk, but

were not statistically significant, likely due to low statistical power. Two studies

indicated non-significant elevated risks of esophageal cancer [30, 63], while one

30

study suggested a protective effect [64]. In addition, all of these studies were

based on mortality rather than incidence. Errors associated with coding of

cause of death can impact risk estimates. Furthermore, all of these studies

compared the observed to the expected numbers that are generated from

external general population. It has been shown that a bias towards

underestimating the mortality risks in occupational cohorts when the general

population is used (i.e., external comparison) as the comparator [65].

Uranium Mining in Ontario

Uranium mining in Ontario first started in 1954 when uranium deposits were

discovered in the areas of Elliot Lake, Agnew Lake, and Bancroft Township.

Mines in Ontario continued operations until 1996, employing over 28,000 men

during this period to extract uranium ores. The health effects associated with

uranium mining in Ontario have been examined previously by the Ham

Commission [66], Muller and colleagues [8-10], and the Industrial Diseases

Standards Panel [38].

Cancer risk associated with exposure to radon and its decay products

have been closely examined by Muller and colleagues. Like in other studies

conducted during this period, standardized ratios were computed for stomach

cancer on two occasions. In the first when follow-up ended in 1977, the SMR for

stomach cancer was 1.3 (95% CI 0.83-2.01), based on 21 deaths. Following the

latest update in 1981, the SMR for stomach cancer increased to 1.41 (95% CI

0.99-2.01) based on 30 deaths. These estimates excluded gold miners who are

31

known to have increased stomach cancer risks due to exposure to arsenic [67].

While the risk for stomach cancer was on an increasing trend, neither analysis

showed a statistically significant relationship with exposure to radon and its

decay products likely due to low precision.

Cancer Risks at Low Doses

Figure 5 compares average cumulative doses of uranium miners in

different cohorts. Of the 11 cohorts, the Colorado Plateau of the United States

had an average of 580 WLM of equivalent radon and its decay products at the

time of the BEIR VI review [1]. In contrast, the Ontario Uranium miners cohort had

an average of 31 WLM. Only Beaverlodge (Canada) and Radium Hill (Australia)

had lower average cumulative doses from radon and its decay products than

the Ontario cohort [1]. Also, in contrast to other cohorts, the Ontario uranium

miner cohort is by far the largest cohort reviewed by BEIR VI committee. The

advantage of having a large cohort is that it is amendable to evaluating

cancer risks at lower doses.

32

Figure 5: Average doses of radon (WLM) and number of miners in different cohorts.

Source: BEIR VI [1].

0 200 400 600

Radium Hill (Australia)Beaverlodge (Canada)

Ontario (Canada)France

Newfoundland (Canada)New Mexico (US)

Czech RepublicPort Radium (Canada)

ChinaSweden

Colorado (US)

Average Working Level Month (WLM)

Ura

niu

m M

iners

Co

ho

rt

Average Working Level Month

0 5,000 10,000 15,000 20,000 25,000

Radium Hill (Australia)Beaverlodge (Canada)

Ontario (Canada)France

Newfoundland (Canada)New Mexico (US)

Czech RepublicPort Radium (Canada)

ChinaSweden

Colorado (US)

Number of Miners Employed

Number of Miners

33

Summary of Review

In summary, the literature on the association between exposure to radon

decay products and cancer risk other than lung is limited. There is some

evidence from other uranium cohort studies that workers may be at increased

risk of gastrointestinal cancer. However, larger numbers of workers and a longer

period of follow-up are required to examine these more rare events. Although

there is a significant body of literature on the long-term consequences of

radiation exposure, for example studies involving the Atomic Bomb Survivors,

these studies focus on the health consequences of a one-time high dose

exposure, in contrast with uranium miners, who may experience relatively high

occupational radiation exposures over a period of several years. The cancer

effects from radiation exposure at lower doses spread over a long period of time

are less clear. The last update of the Ontario Uranium Miners cohort occurred

nearly 25 years ago (in 1981) [9]. The added person-years of follow-up provide

additional statistical power to detect risks associated with exposure to radon

and its decay products.

Scientific and Practical Relevance of this Research

Between 1954 and 1996, over twenty-eight thousand men were employed

to extract uranium ore from vast uranium deposits located in various parts of

Ontario, Canada. During this period, more than 300 million pounds of uranium

34

oxide (U3O8) was extracted from underground mines [68]. With recent increased

energy demands, the remaining uranium reserves in Ontario that were

previously considered to be of too low grade to be economically viable are

once again generating interest in exploration and development [69].

Furthermore, an estimated 50 percent of uranium reserves in the Elliot Lake

region alone remain un-mined [68, 69]. Despite the lucrative past and enormous

potential future economic benefits of this important commodity, the uncertainty

of the inherent adverse health effects associated with mining of uranium ore in

relation to major organs of the gastrointestinal track remain unknown.

A substantial portion of the literature regarding the relationship between

ionizing radiation and cancer focuses on lung cancer mortality. It is not clear

what risks are experienced by workers for other forms of cancer. Collective

scientific evidence from studies conducted to date is suggestive of an increase

in cancer risk of major organs along the gastro-intestinal tract, particularly for

stomach cancer, however, results are in conclusive. The major limitation of these

individual studies has been a lack of statistical power due to the low incidence

rate of gastrointestinal cancers, and for some, low exposure to radon and its

decay products. Given that Ontario uranium miners represent a large cohort

with long period of follow-up, a study of this group may be able to detect

smaller cancer risks if they exist. This is necessary to inform policies and standards

to better protect future workers in this industry.

35

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41

67. Kusiak, R.A., Lung Cancer Mortality in Ontario Gold Miners. Chronic Diseases in

Canada, 1992. 13(No 6 (Suppl)): p. s23-s26.

68. Government of Ontario, Uranium in Ontario, Uranium Mineralization,, Exploration

and Mining in Ontario. 2006, Government of Ontario: Toronto, Ontario, Canada.

69. Cochrane L.B. and Roscoe W.E., Technical Report on the Elliot Lake Project,

Ontario, Canada. 2007, Scott Wilson Roscoe Postle Associates Inc.: Toronto,

Ontario, Canada.

70. Darby, S.C., E.P. Radford, and E. Whitley, Radon exposure and cancers other

than lung cancer in Swedish iron miners. Environ Health Perspect, 1995. 103

Suppl 2: p. 45-7.

Table 5: Summary of miners cohorts in which gastrointestinal cancer risks have been examined. (BEIR VI, p. 83,

131)

Study Author (Year) Population Cancer Site (ICD) SMR (95% CI)

Morrison et.al. (1988)[63]

Study Population

Newfoundland cohort of fluorspar miners (N=4320) Referent Population Mortality rates for Newfoundland by calendar year

Stomach (ICD-8) Large intestine Rectum

1.35 (0.85-2.05) 0.57 (0.18-1.34) 0.33 (0.00-1.84)

Tomasek et.al. (1993)[63]

Study Population

- West Bohemia cohort of uranium miners (N=4320) Referent Population Mortality rates for Czechoslovakia by calendar year

Stomach (ICD-9: 151) Esophagus (150) Colon (152-153) Rectum (154) Non-lung cancers

1.05 (0.79-1.35) 1.22 (0.49-2.51) 0.84 (0.50-1.34) 1.04 (0.67-1.55)

1.14 (0.98-1.33)

Darby et.al. (1995)[70]

Study Population Swedish iron miners Referent Population External rates from communities in the same area

Stomach Rectum

1.45 (1.04-1.98) 1.94 (1.03-3.31)

43

Study Author (Year) Population Cancer Site (ICD) SMR (95% CI)

Darby et.al. (1995)[30]

Study Population Joint analysis of 11 cohorts of miners from different countries Referent Population Rates from general population of respective country

Stomach (ICD-9: 151) Esophagus (150) Colon (152-153) Rectum (154) Non-lung cancers

1.33 (1.16-1.52) 1.05 (0.77-1.41) 0.77 (0.63-0.95) 0.86 (0.66-1.11)

1.01 (0.95-1.07)

Laurier et.al. (2004)[64]

Study Population French cohort of uranium miners employed for at least 2 yrs (N=1785) Referent Population National mortality rate of male population of each calendar year

Stomach (ICD-9: 151) Esophagus (150) Colon/Rectum (152-154)

1.10 (0.50-2.00) 0.70 (0.40-1.40) 1.40 (0.80-2.10)

44

Table 6: Summary of transit time and potential radon doses to the organ based

on the gastrointestinal tract model

OrganTime

(Hours)

Transit Time

(hours)*

Tissue Weighting

Factor (wT)**

# of Half Lives***

Estimated Proportion of

Doses to Organ

Proportion of Time

Oral Cavity 0 0 - 0 0,00% 0,00%Esophagus 0 0 0,05 0 0,00% 0,00%

01 54,55% 3,00%2345 42,61% 10,00%6789

1011121314151617 2,84% 29,00%181920212223242526272829 0,07% 29,00%303132333435363738394041 0,00% 29,00%

Small Intestine

Stomach 1,3

4,7

1,15

4

12

12

0,12

0,05

0,12

0,12

Note: *Transit times based on ICRP-100 updated Human Alimentary Tract Model for Radiological Protectin; **Tissue Weighting Factor based on ICRP-60 for radiosensitivity of organs; *** Number of half live was based on decay chain of short lived radon decay products of 51 mintues.

14,1

14,1

14,10,12

Right Colon

Left Colon

Sigmoid 12

45

Chapter 2: Research Methodology

Chapter 2: Research Methodology

46


Overview ..........................................................................................................................47

Methodology...................................................................................................................48

Overview Study Design...............................................................................................48

Data Sources................................................................................................................48

Data Source 1: Work History File ............................................................................49

Data Source 2: National Dose Registry ...............................................................55

Data Source 3: Ontario Cancer Registry and Ontario Mortality Database..64

Record Linkage............................................................................................................65

Linkage Results .........................................................................................................68

Radon Decay Product Exposure Assignment .........................................................69

Analytic Approach......................................................................................................73

Confounding and Effect Modification.....................................................................75

Latency .........................................................................................................................76

Loss to Follow-up..........................................................................................................76

Chapter 2 References....................................................................................................78

47

Overview

The overall goal of this study is to assess the risk of gastrointestinal cancer

among male workers employed in Ontario uranium mines between 1954 and

1996, and followed through December 31, 2004. Within this cohort, the specific

objectives of this study are as follows:

1) To determine whether the risk of diagnosis (incidence) of or death

(mortality) from gastrointestinal cancers (esophageal, stomach, and

colorectal) is associated with cumulative exposures to radon decay

products; and,

2) To determine whether the duration of exposure (dose rate), years since

last exposure, and age at first exposure modify these associations.

This Chapter describes the methodology needed to address the overall

objectives of this study. Specifically, this Chapter contains detailed descriptions

and/or discussions of the following:

• Rationale for choice of study design;

• Data sources;

• Record linkage results;

• General analytical strategy; and,

• Potential biases.

48

1.0 Methodology

Overview Study Design

This study uses a retrospective cohort design to address the

aforementioned objectives. This design provides the opportunity to study

multiple outcomes (e.g. esophageal, stomach, and colorectal cancers) related

to exposures to ionizing radiation emitted by radon decay products. Though

cancers are rare events, the Ontario Uranium Miners cohort consists of over

28,000 miners with a long period of follow-up, making a cohort design an

appropriate option for assessing risks for rare outcomes (such as cancer).

Furthermore, this cohort’s long follow-up period allows for the opportunity to

examine diseases with long latent periods.

In radiation epidemiology, retrospective cohort design has been the

primary tool for examining cancer risks. This is particularly evident for evaluating

cancer risks of uranium miners who have been exposed to alpha emitting radon

decay products. To date, in addition to Ontario, cancer risks derived from

retrospective cohorts have been examined for many uranium mining cohorts

located worldwide [1-7].

Data Sources

This study uses 4 different data sources to address the research objectives.

The Work History File (WHF) and the National Dose Registry (NDR) were used to

assemble the study cohort and to assess exposure, while the Ontario Cancer

49

Registry (OCR) and the Ontario Mortality Database (OMD) were used to identify

cases (cancer diagnosis and deaths) and to determine person-years at risk.

Table 1 summarizes the contents and purposes of these data sources.

Table 7: Summary of data sources and databases used in the study

Database Data Source/custodian Purpose of Database

Work History File (WHF)

Workplace Safety Insurance Board of Ontario (WSIB)

- Extract of the Mining Master File (MMF);

- Identify cohort members, and;

- Radon exposure data, work history

National Dose Registry

(NDR)

Radiation Protection, Health Canada

- Centralized national database;

- Identify cohort members, and;

- Radon and gamma exposure data, work history

Ontario Cancer Registry (OCR)

Cancer Care Ontario (CCO)

- Identify cancer diagnosis and death (outcome)

Ontario Mortality Database (OMD)

Registrar General of Ontario - Identify fact of death for calculating person-years

Data Source 1: Work History File

The Work History File (WHF) is a subset of the Mining Master File (MMF)

extracted for the purpose of investigating health risks of workers with a history of

uranium mining in Ontario. Information for this data source originated shortly

after the Ontario Mining Act came into effect in 1928. Under this act, miners who

worked in Ontario were required to attend annual chest clinics in order to be

50

certified as being fit to work in dust exposure occupations within the mining

industry [8, 9]. Part of the examination involved collecting detailed work history

of employment in mines from the time of the previous examination (hire) from

each miner. This information was later transcribed onto computer cards and still

later onto computer tapes. Data collection continued until 1986 where it was

discontinued.

Inclusion Criteria for Selecting Uranium Miners from Mining Master File

Extraction of the WHF from the MMF was conducted by one of the co-

authors (G. Suranyi) of the original Muller studies [10-12] for an earlier study of

uranium miners and risk of congenital anomalies in offspring [13]. Miners meeting

the following inclusion criteria in the MMF were extracted [14]:

• Male;

• Miner worked in a uranium mine in Ontario between 1954 to 1986

inclusive; and,

• Miner worked for at least 0.5 months in Ontario uranium mines (Ministry

of Labour's definition of a uranium miner).

The data file contains unique information about each miner (names, date

of birth, place of birth) as well as their work history information. A summary of the

key variables contained in the extracted WHF are shown in Table 2 below with

full record layout of the WHF found in Appendix I. Table 3 shows summary

statistics of the miners captured by the WHF. In total, there were 26,320 miners

51

found in the WHF. Of these miners, 92 were females, 119 had missing information

on sex, and the remaining miners were male. The median year of birth for these

miners was 1937. Of the miners employed in Ontario uranium mines, only 6,701

miners were born in Ontario. A large proportion of miners were born in Quebec

and the Maritimes (Newfoundland and Labrador, New Brunswick, and Nova

Scotia) while 5,794 miners were born outside of Canada.

52

Table 8: Description of main variables of the Work History File

Variable name Description

MCERT Unique Miner Certificate Number

Names Surname/first & second given name

Date of birth Year/Month/Day

Place of birth Place of birth codes

Data on work characteristics

YRS

Year of start of employment each employment

record

MOS

Month & day of start of each employment

record

WLMS

Radiation exposure in WLMs of each

employment record

EMOS Elapse time in months for radiation exposure

MINECD Mine code of each employment record

OREO Ore code of each employment record

ORE_Flag Flag to indicate whether miner was exposed to

other type of ore (e.g., gold mining)

OCCUPO Occupation code of each employment record

53

Table 9: Characteristics of Ontario Uranium Miners from data extracted from the

Work History File (Mining Master File), 1954-1986.


Number of miners 26,320

Sex (n (%))

Males

Females

Missing

26,109 (100)

92 (0)

119

Year of Birth (n (%))

<1900

1900 - 1919

1920 - 1939

1940 - 1959

1960+

Mean

Median

Range

Missing

28 (0.1)

2,298 (8.8)

12,681 (48.6)

10,140 (38.9)

953 (3.7)

1937

1937

1887-1984

220

Place of birth (n)

Newfoundland

Prince Edward Island

Nova Scotia

New Brunswick

Quebec

Ontario

Manitoba

Saskatchewan

Alberta

British Columbia

North West Territories

Yukon

Canada (region not specified)

All of Canada

Outside of Canada

Missing

481

37

493

438

2,938

6,701

208

165

59

97

5

6

8,650

20,278

5,794

248

54

Strengths and Limitations of the Work History File

Data from the Work History File (WHF) has been used extensively in the

past for etiologic research [8, 9, 15-17] and litigation purposes. As such, the

quality of the WHF has been well scrutinized. For example, the WHF was

previously assessed, both for completeness and validity of the work history data

[18]. Employment records from 3 mining companies were randomly sampled

(n=288) and compared to the information contained in the WHF. The inclusion

rate was 99%. Of the matched files, 100 were randomly selected and the work

history information from the WHF was compared to respective company payroll

records. No significant differences were observed between company records

and information from the WHF [18].

Despite the wealth of information contained in the WHF, it has its

limitations. Though uranium mining remained active in Ontario until 1996, the

WHF was officially terminated in 1986. In fact, data for 1986 in the WHF is

relatively incomplete. Termination of the WHF resulted in a data gap for miners

employed in uranium mines between 1987 and 1996. Secondly, information on

potential confounders that would have been relevant to cancers of the

gastrointestinal tract (e.g., smoking, diet, H. pylori infection) was not collected

since the WHF was not originally designed for use in epidemiological

investigations.

55

Data Source 2: National Dose Registry

The National Dose Registry (NDR) is maintained by the Radiation

Protection Bureau of Health Canada. It is a national and centralized registry with

the mandate to monitor radiation doses of all workers employed in Canada

who are potentially exposed to ionizing radiation. Though established in 1987,

the NDR contains information dating back to the early 1950s [17]. The NDR and

its use for epidemiological studies are described in a number of publications [19-

27]. Since it is a national and centralized database, it can monitor and collect

exposure information on individual workers even if s/he moves to another

province and/or changes jobs.

Uranium miners are among the group of workers monitored by the NDR.

Radon dose records for uranium miners were in part, reconstructed,

retrospectively beginning in 1978 based on a number of different data sources.

Before 1968, radon dose (WLM) data for individual miners was obtained from

magnetic tapes provided by the Ontario Worker’s Compensation Board and the

Ontario Ministry of Labour. These records were supplemented with employment

records from Elliott Lake uranium mines. By the early 1970s, dose data was

obtained directly from mining companies. A more detailed description of the

dose data from the NDR is described in the proceeding sections of this Chapter

and Chapter 4.

56

Inclusion Criteria for Selecting Uranium Miners from National Dose Registry

In this study, data for uranium miners employed in Ontario were extracted

from the entire NDR. Miners meeting the following criteria (original letter in

Appendix 1) were extracted for analysis:

• All individuals who had ever worked in an Ontario uranium mine;

• Period between 1951 (inception of the NDR) to December 31st, 2004;

• All information on radiation exposure (e.g., radon, gamma, and

others) ; and,

• Complete work history (all job classifications including work in another

occupations with potential exposure to ionizing radiation and province

of employment).

Two data files were obtained from the National Dose Registry for analysis

in Microsoft Access format. The first data file (“Cohort File”) contained unique

identifiers1 (first and last names), date of birth, place of birth, and sex of the

miner. In total, there were 29,888 entries representing 29,888 workers identified in

the NDR. However, among these workers 23 duplicates were found resulting in

29,865 miners eligible for analysis (Table 4). The second data file (“Dose File”),

also in Microsoft Access format, contained employment and dosimetry

information. In total, 210,791 employment records were identified for the

corresponding 29,865 workers. A summary of the content of the data extracted

from the Cohort File and Dose files of the NDR are shown in Table 4.

1 Note: Due to privacy obligations, the author does not have access to unique identifier information. Only Mr Nelson Chong who needs this information for record linkage purposes were privy to personal identifiers.

57

Table 10: Description of variables extracted from the National Dose Registry.


Cohort File (n=29,865 (after removing 23 duplicate miners))

Names Surname/first & second given name

Date of birth Year/Month/Day

Place of birth Place of birth codes

Dose File (n=210,791 employment records)

EXPOSURE_YEAR Calendar year of exposure (employment)

MAXJC Job class

EXTREMITY_CODE Code for type of exposure (radon or gamma)

PROVINCE Province/territory of employment

GROUP_CLASS Industry

SERVICE_TYPE Type of dosimetry service

SERIAL_NUMBER Employer code

JOB_CLASS Code for job classification

SKIN_DOSE_FIELD Alpha exposure (radon, WLM)

FROM_PERIOD First period of monitoring

TO_PERIOD Last period of monitoring

RECORD_COUNT No. of discrete dose records per year

Descriptive Statistics from the National Dose Registry

In total, the NDR contained 210,791 records describing the characteristics

of 29,865 eligible miners (Table 5). According to the NDR, 96 percent of the

miners were male miners with the remaining being either female (2 %) or

unknown (2%). The miners were born between 1887 and 1979, more than half of

the miners were born before 1940. Although some information on place of birth

58

was available in the NDR, however, most was missing (n=21,705). Among those

with known place of birth information, the majority were born in Canada

(n=7,451). As expected, Ontario was the most common known province of

birth.

Strengths and Limitations of the National Dose Registry

One of the major strengths of the NDR is the completeness of the data in

terms of the uranium mining periods in Ontario spanning from 1954 to 1996.

Secondly, the NDR being a national database in scope records doses accrued

outside of Ontario. Furthermore, the NDR also includes doses from all

occupations requiring radiation monitoring and not just uranium mining. Like the

WHF, data quality of the NDR has been well scrutinized particularly for radiation

doses. Spot checks were conducted by the NDR and the Atomic Energy Control

Board of Canada (AECB) for accuracy of the reported doses and discrepancies

investigated between different data sources.

As with most databases, there are limitations to the NDR. One of the major

limitations (from an epidemiological perspective) is the use of periods to code

start and end dates. Up until 1977, the NDR divided a calendar year into 26 two

weekly reporting periods in order to code for the time interval in which the

exposure occurred. In 1977, this was simplified to 24- semi monthly reporting

periods. For uranium miners, doses were reported on a quarterly basis (4 times

per year). The quarters were defined as follows:

• 1st quarter of the calendar year - 06

59

• 2nd quarter of the calendar year - 12

• 3rd quarter of the calendar year - 18

• 4th quarter of the calendar year - 24

Given this coding, the exact dates of exposure could not be determined.

Furthermore, start and end dates of a given year for a significant proportion of

miners could not be determined with certainty.

Like the MMF, the NDR was created for regulatory purposes. In the case of

the NDR, the objective was to collect information on radiation exposure for

workers in Canada. As such, information on potential confounders that would

have been relevant to cancers of the gastrointestinal tract (e.g., smoking, diet,

H. pylori infection) is not available.

60

Table 11: Characteristics of Ontario Uranium Miners from data extracted from

the National Dose Registry (as of December 31, 2004).



Sex (n (%))

Males

Females

Unknown

Missing

28,786 (96)

486 (2.0)

593 (2.0)

24


<1900

1900 - 1919

1920 - 1939

1940 - 1959

1960+

Mean

Median

Range

Missing

25 (0.1)

2,178 (7.6)

12,787 (44.4)

11,818 (41.0)

1,989 (6.9)

1940

1938

1887-1979

1,068

Place of birth (n)

Newfoundland

Prince Edward Island

Nova Scotia

New Brunswick

Quebec

Ontario

Manitoba

Saskatchewan

Alberta

British Columbia

North West Territories

Yukon

Canada (region not specified)

All of Canada

Outside of Canada

Missing

230

12

117

153

692

2,780

93

70

23

34

1

1

3,245

7,451

709

21,705

61

Comparison of the Work History File and National Dose Registry

While there are many similarities between the Work History File (WHF) and

the National Dose Registry (NDR), there are some important differences in terms

of the quality and the completeness of the data. Tables 6 and 7 compare and

contrast the WHF with the NDR with respect to individual identification

information as well as work history and exposure information. Table 6 shows

information on unique identifiers of the miners, which is important for record

linkage purposes. In both data sources, names (first and given) and date of birth

were relatively complete.

Approximately 73% of place of birth were missing in the NDR while the

same information was 99% complete in the WHF. Discussions with

representatives of the NDR revealed that data entry of place of birth only

began recently. Furthermore, the NDR developed and used its own codes for

place of birth rather than using the standard coding from the Vital Statistics

Section of Statistics Canada. From the perspective of record linkage, different

coding systems create difficulties when matching different records for the same

miner.

62

Table 12: Qualitative comparison of unique identification of uranium miners

found in the Work History File and National Dose Registry

Databases

Criteria Work History

File (WHF)

National

Dose

Registries

(NDR)

Comments

Unique Identifiers of Miners

Surname √ √ Available in both databases*

Given Name 1 √ √ Available in both databases*

Given Name 2 √ √ Available in both databases*

Date of Birth (year) √ √ Available in both databases

Date of Birth (month) √ √ Available in both databases

Date of Birth (Day) √ √ Available in both databases

Place of Birth

√ ≈

WHF was more complete (99%

complete) and uses standardized

coding system. Seventy-three

percent of place of birth in the

NDR was missing.

Note: √ - Available (>90%); ≈ - Available but limited; ≠- Not Available; *-Information obtained

from N Chong

Table 7 presents a qualitative comparison of the work history and

dosimetric information found in the WHF and the NDR. In terms of coverage, the

NDR has 14 more years of information than the WHF. Given that mines operated

until 1996, the added years provided additional data for those who worked

beyond 1986 and those who started on or after 1986. Although the years of

employment are available in both data sources, the NDR lacked details in terms

of start day and month of employment.

63

Table 13: Qualitative comparison of work history and dosimetry information

uranium miners found in the Work History File and National Dose Registry

Databases

Criteria Work History

File (WHF)

National

Dose

Registries

(NDR)

Comments

Work History Information of Miners

Coverage (uranium

miners) 1954-1986 1954-2004

NDR data was more up to date

and complete relative to WHF.

Year of employment √ √ Calendarized year of employment

used in both databases.

Month and Day of start

of employment

√ ≠

Due to the quarterly reporting

mechanism of the NDR, month

and day of start of employment

cannot be determined with

certainty.

Job classification

√ ≈ Although job codes were

available in the NDR, accuracy of

the coding was questionable.

Mine employed

√ ≈

Although the NDR has a serial

number that identifies the

company (mine operator), the

exact mine (mine name) in which

the miner could not be

determined with certainty.

Flag to indicate

exposure to other types

of mining √ ≠

WHF has some information on

exposure to other types of mining

(e.g., gold, copper, nickel etc.)

Dosimetry

Radon Exposure √ √ Available in both data bases.

Gamma Exposure ≠ ≈ The NDR has gamma

measurement starting 1981.

Note: √ - Available (>90%); ≈ - Available but limited; ≠- Not Available

64

Data Source 3: Ontario Cancer Registry and Ontario Mortality Database

The Ontario Cancer Registry (OCR) is a population-based registry

containing information on all Ontario residents who have been diagnosed with

cancer (incidence) or who have died of cancer (mortality). The OCR depends

entirely on information generated for purposes other than cancer registration

and is created by record linkage and computerized medical logic. The major

data sources used to create the OCR are:

• Hospital separations data with cancer as a diagnosis;

• Pathology reports with a mention of cancer;

• Death certificates in which cancer is the underlying cause of death; and,

• Reports from specialized cancer centers throughout the province.

The Ontario Cancer Registry also uses the Ontario Mortality Database to

record fact of death for cancer cases. Relevant data holdings at the OCR

include the following:

• Deaths with cancer as cause of death (1950-2004);

• Deaths from all causes (1964-2004); and,

• Cancer diagnoses (new cases, 1964-2004).

Non-melanoma skin cancers are not captured by the OCR. The quality and

completeness of the OCR for coverage of Ontario cases has been previously

examined and is considered to be of good quality comparable to leading

cancer registries worldwide. More detailed information regarding the quality of

the OCR is available in an IARC monograph [28].

65

Data Source 4: Ontario Mortality Database

For every death in Ontario, a death certificate must be submitted to the

Office of the Registrar General (ORG) in accordance with the Vital Statistics Act.

The data are coded and entered at the ORG. A copy of this file was provided

to the Ontario Cancer Registry. This file was used to determine the fact and date

of death to permit determination of person years at risk of cancer.

Record Linkage

Record linkage refers to the process of linking records within or between

different data sources to the same entity. It is a tool commonly used for passive

follow-up of cohort members to determine health outcomes being investigated

[29]. In this study, record linkage was used to assemble a cohort of uranium

miners from the WHF and the NDR. Miners’ cancer and vital status were

determined by linkage to the OCR, and OMD databases, respectively. This was

achieved using deterministic and probabilistic linkage methods followed by

manually resolving grey areas pairs (uncertain matches). Unique identifiers used

in the linkage process were phonetically encoded names, surname and given

name(s), date of birth, and gender. Other information such as place of birth

(where available) was used to resolve grey areas. These unique identifiers were

also used to identify diagnosis and death for the OCR and OMD respectively.

Figure 1 summarizes the linkage flow. The Work History File and the National

Dose Registry were previously linked in 2003 to examine risks of congenital

66

abnormalities [13, 30]. This initial linkage was expanded for the current study to

include 1986 to 2004 in order to capture additional miners employed after 1986

to form the study cohort. The cohort was then linked to the Ontario Cancer

Registry to identify all cohort members that had been diagnosed with or died

from cancer. The same cohort was also linked to the OMD to identify deaths

from non-cancer causes.

67

Figure 6: Summary schema for record linkage of different data sources used to

establish the cohort, exposure history, outcome identification, and follow-up

data.

68

Linkage Results

To avoid potential biases, it was determined a priori that the current author

of this study was not to be involved in any work related to linking information

from different data sources or in the resolution of grey areas of the linkage

process for individual uranium miners. Instead, record linkage was conducted by

N Chong, a Research Associate at Cancer Care Ontario who had many years

of experience in conducting linkage work. It is also important to note that Mr.

Chong was also blinded to the exposure information during linkage to the

outcome databases, as well as to any information regarding linkages

conducted previously by Muller and colleagues [10, 11].

Between the Work History File and the National Dose Registry (Table 8),

30,914 workers were identified. Of these, 82 percent (n=25,271) have

employment information appearing in both the WHF and the NDR, 15 percent

(n=4,594) are only in the NDR only and 3 percent (1,049) are only in the WHF. A

higher proportion of miners found in the NDR than the WHF was expected given

that the WHF was terminated in 1986 while the NDR continued until 2004.

69

Table 14: Cross-tabulation of number of miners found in the National Dose

Registry and Work History File

Radon Decay Product Exposure Assignment

Exposure to radon decay products was measured within the mines using

equivalent units of Work Level (WL) of energy from alpha particles emitted

potential from decay of radon-222 (222Rn) in air. One WL has an equivalent

energy of 1.3 x 10^6 million electron volts per liter of air. Exposure to one WL in a

period of one month (assumed to be 170 hours) equals an exposure to radon

and its decay products of one Working Level Month (WLM). That is, if a miner is

exposed to 2.6x10^6 million electron volts (2 WL) in 170 hrs, then the miner is said

to have been exposed to an equivalent of 2 WLM for that particular month .

In Ontario, over 131,000 area measurements of radon and its decay

products were taken since mines began operation [10]. However, during the 43

years of mining in Ontario (1954-1996), methods and frequency of

measurements changed. Similar to practices around the world [31, 32],

measurements of radon and its decay products were conducted ad hoc in the

Yes No TotalYes 25.271 1.049 26.320No 4.594 0 4.594

Total 29.865 1.049 30.914

National Dose Registry

Wor

k H

isto

ry

File

70

early years and gradually became more systematic and frequent in later years.

Table 9 summarizes the different approaches used to measure radon decay

products for different periods and the associated uncertainties with these

measurements.

Although uranium mining in Ontario began in 1954, systematic monitoring

of radon levels did not begin until 1958. Prior to 1958, extrapolation methods

were developed by mine engineers, industrial hygienists, and government

officials who had intimate knowledge of mining construction, and processes of

the time [10, 11]. Beginning in 1958, radon levels were measured by mine

operations using the Kusnetz method [33] with instrumentation calibrated by

government authorities. Levels of radon and its decay products were measured

every 3 to 4 months. No individual measurements were undertaken; but rather,

measures of radon and its decay products were obtained in headings, stopes,

raises, and travelways. Exposure to radon daughters and its decay products

were calculated by the time-weighted average for the concentration of work

area (stopes, headings, raises, and travelways) with the relative time-weights of

80 percent for work areas and 20 percent for travelways [11]. These weighted

averages were used to assign individual exposures by multiplying the average

weighted concentration of radon and its decay products in the mine during the

year the miner worked by the number of months employed during that year.

These estimates were adjusted for overtime, work stoppages, strikes, and

holidays throughout the year[11].

71

Beginning in 1968, individual exposures based on a detailed work history

(location and duration of a given day) and corresponding mine measurements

of radon decay products were reported by the mine operator directly to the

Atomic Energy Control Board (AECB) of Canada. Measures of radon and its

decay products occurred much more frequently and at different locations

within the mine. Individual exposures were assigned based on miners’ daily

reports of the time spent in each workplace and most recent measurements of

the levels of radon and its decay products closest to the corresponding

workplaces. Data on radon decay products have been collated over the years

by various stakeholders, namely, Ministry of Labour, AECB and mine operators,

and are currently housed in the WHF and NDR used for this study.

72

Table 15: Overview of dosimetry practices for measurement of radon and its

decay products for Ontario Uranium Miners, 1954-1996.

Period Dosimetry Practice Qualitative

Uncertainty Level*

• 1954-1957 • No measurements, estimates by

extrapolation methods

developed by mine engineers

and other experts. Miner

exposures were assigned based

on extrapolations.

• 1958-1968 • Area measurements conducted

by mine operators using

equipment calibrated by

government authorities.

Measurements were taken

every 3 to 4 months.

• 1968+ • Starting in 1968, radon

measurements were taken on a

regular basis and in different

locations within a mine. Work

history of miners was collected

on a daily basis. Miner

exposures to radon and its

decay products were

determined based on the

closest area(s) in which the

most recent measurements

were taken.

Higher

Uncertainty

Lower

Uncertainty

Note: *Uncertainty level is a qualitative assessment of the potential for measurement error of

radon and its decay products. ‘Higher Uncertainty’ indicates higher potential for

measurement error than ‘Lower Uncertainty’.

73

Analytic Approach

Internal comparison method based Poisson regression of grouped data

(risk-set approach) is one of the primary approached used to evaluate cancer

risks in occupational epidemiology [34-36]. Person-years were tabulated using a

program developed by Pearce and Checkoway [37] and modified by

Villeneuve and colleagues [38, 39]. Person-time data was generated for each

individual starting at the date of first employment in any Ontario uranium mine

(entry date) until December 31, 2004 or date of death/diagnosis of cancer

(esophagus/stomach/colorectal) or whichever occurred first. These person-

years were cross-classified by independent variables. An example2 [40] of the

cross-tabulation (risk sets) for 3 exposure levels and three age groups is shown in

Table 10.

2 Examples adapted from course notes from Dr. Paul Corey.

74

Table 16: Cross tabulations of 3-category exposure variable by 3-category age

groups

Exposure Categories Age Group (years)

Low Medium High

< 25

c11

PY11

r11 = c11/py11

c12

PY12

r12 = c12/py12

c13

PY13

r13 = c13/py13

25-<65

C21

PY21

r21 = c21/py21

c22

PY22

r22 = c22/py22

c23

PY23

r23 = c23/py23

65+

c31

PY31

r31 = c31/py31

c32

PY32

r32 = c32/py32

c33

PY33

r33 = c33/py33

Note: C- cases (diagnosis or deaths); PY – Person years at risk; and r= rate.

75

As in studies conducted recently [39, 41], a Poisson regression model was

used to conduct an internal cohort comparison. Poisson regression models the

logarithm of either the incidence and mortality rates of GI cancers as a

regression of the independent variables. Relative risks were estimated by

exponentiation of the regression coefficients for the independent variables. The

general form of the Poisson regression model is:

λ /λo = exp (β1X1, β2X2, …, βkXk), (3)

where X1, X2, …,Xk, are predictor variables;

λ is the incidence/mortality rate for persons with specified values X1, X2, …,Xk;

λo is the baseline mortality/incidence rate; and,

β1, β2, …, βk are parameters to be estimated from the data.

Cumulative dose (WLM) for each miner was treated as a time-dependent

variable in the internal comparison. The goodness of fit of the model was

assessed with the ratio of the deviance to the number of degrees of freedom.

Confounding and Effect Modification

In the modeling process, the potential influence of confounding factors

are typically explored by the change of 10% in the risk estimate as proposed by

Greenland [42]. However, the ability to fully assess and adjust for confounding

effects was limited in this study due to the lack of data on smoking, diet,

physical activity and medical history (e.g., H. pylori infection, stomach ulcers,

Barrett’s esophagus, etc).

76

In lung cancer mortality analyses, duration of exposure (dose rate), years

since last exposure, and age at first exposure have been shown to modify the

dose response relationship. In this study, potential effect modification of these

factors will also be explored. The strategy to be used is by stratification rather

than including it as an interaction term since it is more practical given the

grouped data approach of data analysis.

Latency

Rothman (1981) [43] defined latency as the period between disease

initiation and manifestation. For cancer outcomes, this period can be anywhere

from 5 years for leukemia to 30-40 years for mesothelioma. Given that there is no

consensus on the exact period between initiation and detection, the current

study addresses the issue of latency by lagging the cumulative dose for each

individual in a risk set to the dose received 0, 5, 10, 15, and 20 years before the

event (diagnosis or death due to GI cancer).

Loss to Follow-up

One major limitation of cohort studies in general, is the loss-to follow-up (or

misclassification of disease status) of cohort members. For example, Woodward

and colleagues conducted a retrospective cohort study of uranium miners

employed at Radium Hill in Australia to examine the risk of lung cancer mortality

associated with exposure to radon decay products [7]. Although they found a

significant excess risk of lung cancer mortality (SMR=1.94, 95% CI 1.42-2.45), when

77

the analysis was restricted to those with cumulative exposure greater than 40

WLM, the risk increased by 5-fold (SMR 5.2, 95% 1.8-15.1). Despite the positive

findings, this cohort experienced a loss-to-follow-up of 36%. One of the main

reasons cited for this loss was emigration of migrant workers returning to their

native countries post-war [7].

The Ontario cohort is not immune to loss of follow-up. In fact some loss was

expected given that outcome data (e.g., cancer diagnoses, deaths) were

ascertained from provincial rather than national databases. However, logistical

(time required) and cost considerations made linkage to the national database

prohibitive. The extent of the loss was expected to be approximately 15% given

the experiences of other occupational linkage studies recently conducted in

Canada. For example, Villeneuve conducted a record linkage of the

Newfoundland fluorspar miners to the Canadian Mortality Database in 2005 [41].

Newfoundland is a relatively small province (1.5 % of the population of Canada)

with a highly mobile workforce. Results from their linkage showed that 16% of

deaths due to lung cancer occurred outside of the province of Newfoundland.

The potential biases associated with loss in this study are addressed in the next

Chapter (Chapter 3).

78

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3. Rogel, A., et al., Lung cancer risk in the French cohort of uranium miners. J

Radiol Prot, 2002. 22(3A): p. A101-6.

4. Roscoe, R.J., An update of mortality from all causes among white uranium

miners from the Colorado Plateau Study Group. Am J Ind Med, 1997. 31(2): p.

211-22.

5. Tirmarche, M., et al., Mortality of a cohort of French uranium miners exposed to

relatively low radon concentrations. Br J Cancer, 1993. 67(5): p. 1090-7.



Res, 1994. 137(2): p. 251-61.

7. Woodward, A., et al., Radon daughter exposures at the Radium Hill uranium

mine and lung cancer rates among former workers, 1952-87. Cancer Causes

Control, 1991. 2(4): p. 213-20.

8. Kusiak, R.A., et al., Mortality from lung cancer in Ontario uranium miners. Br J

Ind Med, 1993. 50(10): p. 920-8.

9. Kusiak, R.A., et al., Carcinoma of the lung in Ontario gold miners: possible

aetiological factors. Br J Ind Med, 1991. 48(12): p. 808-17.

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10. Muller, e.a., Study of Mortality of Ontario Uranium Miners 1955-1977. 1983,






Toronto.

12. Muller, J., et al., The Ontario Miners Mortality Study, in Radiation Hazards In

Mining: Control, Measurement, And Medical Aspects M. Gomez, Editor. 1981. p.

Chapter 56 (p.359-362).

13. Nahm, S., Paternal Exposure to Ionizing Radiation in Ontario Uranium Miners

and Risk of Congenital Anomaly in Offspring: A Record Linkage Case-Control

Study. 2003, University of Toronto: Toronto.

14. Nahm, S., Inclusion Criteria for Mining Master File (Perconal communication-

Email). 2006: Toronto.

15. Kusiak, R.A., Lung Cancer Mortality in Ontario Gold Miners. Chronic Diseases in

Canada, 1992. 13(No 6 (Suppl)): p. s23-s26.


Med, 1993. 50(2): p. 117-26.





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18. Industrial Disease Standard's Panel, Report to the Workers Compensation Board

on the Ontario Gold Mining Industry. 1987: Toronto, Ontario. p. (Section 2:

Validity of the Mining Master File).

19. Ashmore, J.P., The Design of National Dose Registries. European Journal of

Cancer, 1997. 33(Suppl.): p. S44-S47.

20. Ashmore, J.P. and D. Grogan, Record Keeping in the Canadian National Dose

Registry. Health Phys, 1977. 33(6): p. 673.

21. Ashmore, J.P. and D. Grogan, Record Keeping in the Canadian National Dose

Registry. Radiation Protection Dosimetry, 1985. 11(2): p. 95-100.

22. Ashmore, J.P., et al., First analysis of mortality and occupational radiation

exposure based on the National Dose Registry of Canada. Am J Epidemiol,

1998. 148(6): p. 564-74.

23. Hazelton, W.D., et al., Biologically based analysis of lung cancer incidence in a

large Canadian occupational cohort with low-dose ionizing radiation exposure,

and comparison with Japanese atomic bomb survivors. J Toxicol Environ Health

A, 2006. 69(11): p. 1013-38.

24. Sont, W.N., et al., First analysis of cancer incidence and occupational radiation

exposure based on the National Dose Registry of Canada. Am J Epidemiol,

2001. 153(4): p. 309-18.

25. Teschke, K., et al., Estimating nurses' exposures to ionizing radiation: the elusive

gold standard. J Occup Environ Hyg, 2008. 5(2): p. 75-84.

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26. Zablotska, L.B., J.P. Ashmore, and G.R. Howe, Analysis of mortality among

Canadian nuclear power industry workers after chronic low-dose exposure to

ionizing radiation. Radiat Res, 2004. 161(6): p. 633-41.

27. Zielinski, J.M., et al., Decreases in occupational exposure to ionizing radiation

among Canadian dental workers. J Can Dent Assoc, 2005. 71(1): p. 29-33.

28. Black, R.J., L. Simonato, and H. Storm, Automated Data Collection in Cancer

Registration. IARC Technical Publication No. 32. 1998, International Agency for

Research on Cancer: Lyon.

29. Howe, G.R., Use of computerized record linkage in cohort studies. Epidemiol

Rev, 1998. 20(1): p. 112-21.

30. Marrett, L. and S. Nahm, Ontario Miners Database Feasibility Study. 2001,

Canadian Nuclear Safety Commission: Ottawa.


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32. Puskin, J.S. and A.C. James, Radon exposure assessment and dosimetry

applied to epidemiology and risk estimation. Radiat Res, 2006. 166(1 Pt 2): p.

193-208.

33. Kusnetz, H.L., Radon daughters in mine atmospheres; a field method for

determining concentrations. Am Ind Hyg Assoc Q, 1956. 17(1): p. 85-8.



35. Checkoway, H., N. Pearce, and D. Kriebel, Research Methods in Occupational

Epidemiology, 2nd Edition. 2004, New York: Oxford University Press. p.91.

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36. Frome, E.L. and H. Checkoway, Epidemiologic programs for computers and

calculators. Use of Poisson regression models in estimating incidence rates and

ratios. Am J Epidemiol, 1985. 121(2): p. 309-23.

37. Pearce, N. and H. Checkoway, A simple computer program for generating

person-time data in cohort studies involving time-related factors. Am J Epidemiol,

1987. 125(6): p. 1085-91.

38. Villeneuve, P.J., R.S. Lane, and H.I. Morrison, Coronary heart disease mortality

and radon exposure in the Newfoundland fluorspar miners' cohort, 1950-2001.

Radiat Environ Biophys, 2007. 46(3): p. 291-6.



Phys, 2007. 92(2): p. 157-69.

40. Corey, P., Random Counts and the Poisson Probablity Model. 2004, University of

Toronto: Toronto.




42. Greenland, S., Modeling and variable selection in epidemiologic analysis. Am J

Public Health, 1989. 79(3): p. 340-9.

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253-9.

83

Appendix 1: Letter Sent to the National Dose Registry to Request Data

Dr. Willem Sont Head, Analysis Unit National Dose Registry Radiation Protection Bureau 775 Brookfield Road, AL 6302C2 Ottawa, ON, K1A 1C1 08 May 2006 Re: Access to National Dose Registry for funded study “Radiation Exposure and Risk of Cancer among Ontario Uranium Miners: a Case-Cohort Study” Dear Dr. Sont: I am requesting access to data held by the National Dose Registry (NDR) to complete a study jointly funded by the Canadian Institutes for Health Research and Workplace Safety & Insurance Board, entitled, “Radiation Exposure and Risk of Cancer among Ontario Uranium Miners: a Case-Cohort Study”. The purpose of this study is to examine cancer risks associated with exposure to ionizing radiation among a cohort of Ontario uranium miners. NDR data will be used to identify potential eligible cohort members and to assess exposure. We have received approval from Health Canada’s REB Secretariat for access to the data contained in the NDR for this study. (See letter attached) This study involves linkage of NDR to the Mining Master File (MMF) for the period of 1950s to the present. The linkage is necessary for the following reasons:

• To identify all individuals who have ever worked in Ontario as a uranium miner; and, • To obtain exposure information (ionizing radiation and work history) for these individuals.

It has come to our attention that previous work for a study of the Eldorado Uranium Miners in Saskatchewan resulted in identification of duplicates of nominal rolls and improvements in exposure information, that these improved data were incorporated into the NDR (personal communication with Rachel Lane, CNSC). We request that these data be included in the version of the NDR provided, if at all possible, as these will improve the quality and accuracy of both our cohort and exposure estimates. Could you please let us know whether the file provided includes these data? Thank you in advance for your attention to this data request. If you have questions, please do not hesitate to contact me at anytime. Sincerely, Loraine D. Marrett, PhD Senior Scientist, Division of Preventive Oncology, Cancer Care Ontario

84

Inclusion Criteria 1. All individuals who have ever worked in an Ontario uranium mine 2. Period between 1951 (inception of the NDR) to the present 3. All information on radiation exposure (e.g., radon, gamma, and others) 4. Complete work history (even if the miner employed in another occupation) 5. All geographical locations of other work (including those outside of Ontario)

Data elements: Identifying variables

1. Social Insurance Number: (9 digit numeric series) 2. Last Name: 3. Given Name1(s): (complete, no initials) 4. Given Name2 (s): (complete, no initials) 5. Sex: 6. Job: (title of the individual’s job, e.g., underground miner) 7. Job class: NDR job classification code 8. Date of Birth: 9. Place of Birth: (province within Canada or Country outside Canada)

Data elements: Dosimetric variables

1. Enroll year: (1st year of radiation exposure) 2. Employment data: (For each job held by miner: job titles/classifications, by date,

employer, location, mine etc) 3. All Extremities: (Whole Body/Torso Head/Collar), Left Hand or Arm (below elbow),

Right Hand or arm (below elbow), Left Foot or Leg (below knee), Right Foot or Leg (below knee))

4. grp-no: geographic, organization & employer code a. prov-cd: province code b. grp-cls: organization code c. groupno: employer code d. svc-type: radiation badge service type e. ser-no: name of the employer

5. frst cont period: First radiation badge wearing period 6. last cont period: Last radiation badge wearing period 7. complete exposure-yr: exposure year to radiation 8. complete dose count: # of radiation records/year 9. complete skin dose: radon dose (WLM) (Note: finest breakdown available

(weekly/monthly/quarterly/yearly)) 10. complete body dose: gamma dose (mSv) (Note: finest breakdown available

(weekly/monthly/quarterly/yearly))

Additional data from the Eldorado Miners of Saskatchewan As available

85

Chapter 3: Assessment of the Impact of loss to Follow-up

Chapter 3: Comparison of Current AND Muller Linkage:

Assessment of Impact loss to Follow-up (1964 -1981)

86

Chapter 3 Table of Contents Assessment of Impact loss to Follow-up (1964 -1981)................................................85

Abstract ............................................................................................................................87

Objectives ........................................................................................................................91

Methodology...................................................................................................................92

Overview.......................................................................................................................92

Definition of Mechanisms of Loss to Follow-up........................................................93

Data Sources................................................................................................................95

Study population .........................................................................................................96

Study Period..................................................................................................................96

Outcomes of Interest ..................................................................................................96

Exposures of Interest....................................................................................................98

Statistical Analysis ........................................................................................................98

Results..............................................................................................................................101

Part 1: Comparison of Current and Muller Record Linkage Results...................101

Part 2: Determination of Potential Biases: Current Study vs. Combine Linkage

......................................................................................................................................108

Chapter 3 References..................................................................................................115

87

Abstract

Background

Loss to follow-up is a methodological challenge for any cohort study. This

is particularly true for computerized record linkage cohort studies where status of

cohort members is determined passively by linking to existing databases. For

example, the Current Study relies on the Ontario Cancer Registry and the

Mortality Database to identify cancer deaths and other causes of death.

Cohort members leaving Ontario represents a loss to follow up due to out-

migration since their health status can no longer be monitored. It has been

shown that if this loss occurs at random, then the resulting risk estimates remains

unbiased. However, if the loss does not occur at random, the resulting risk

estimate will be biased. Since the Current Study uses provincial rather than

national databases to identify events of interest, loss due to out-migration is

expected. As such, the impact on the risk estimate must be explored for this

study.

Objective

The objective of this Chapter is to assess the impact of loss to follow-up by

determining the changes the relative risk of death due to gastrointestinal cancer

based on results of linkage conducted using provincial (Ontario) outcome data

from the risk estimates derived using current linkage results supplemented with

data from national linkage.

88

Methodology

Results of the linkage from the Current Study with provincial cancer and

mortality (fact of death) databases were supplemented with the Muller linkage

which was previously linked to the Canadian Mortality Database for the period

between 1954 and 1981. The impact of the loss was examined by the

magnitude of the differences in the proportion of loss between exposure strata

(exposed vs. non-exposed) and corresponding relative risks were computed for

the Current Study and the Combined analysis (Current deaths + deaths missed

from Muller linkage) for the period between 1954 and 1981.

Results

Between 1954 and 1981, 25,834 miners were employed to extract uranium

ore in Ontario. Of these, 1,227 deaths (all causes) were identified in the Current

Study while 1,947 deaths were identified in the Muller Study. The Combined

Linkage (Current + Muller linkage combined) yielded 2,097 deaths.

For cancer outcomes, there were 297 deaths identified in the Current

Study compared to 415 identified in the Muller Study, a 40% loss in follow-up.

Proportionally, more deaths occurred in the early years than recent years.

Missing deaths occurred more frequently in the lower exposed group

(cumulative radon decay and duration of employment) than higher exposure

group.

Conclusion

89

Linking to the provincial rather than national outcome database resulted

in a loss of follow-up of 40% of deaths from all causes. Deaths appeared to

occur more frequently in the lower exposure group.

Introduction

Occupational cohorts constructed by linking existing administrative

databases have been invaluable in addressing research questions related to

the potential adverse health impacts associated with exposure to occupational

and environmental hazards [1-7]. Since first introduced in 1959 by Newcombe

and colleagues [3], the practice of Computerized Record Linkage (CRL) based

on probabilistic principles has became increasingly popular for a number of

reasons. From a methodological perspective, refinement of linkage algorithms

has improved the sensitivity and specificity of matches between different data

sources [1, 2] reducing the number of potential errors and thereby improving the

validity of linkage studies. From a statistical perspective, CRL can be used to link

large databases which provide the necessary statistical power to detect small

increases (or decreases) in relative risks associated with low level exposures to

environmental or occupational hazards. Finally, from a practical perspective,

CRL studies relying on existing data result in lower costs than studies involving

data collection from large numbers of individuals.

Despite the many advantages, CRL studies have limitations. One major

limitation of CRL studies is the reliance of passive follow-up to identify events of

interest (e.g., cancer deaths) and those remaining at risk of developing the

90

event. In passive follow-up, events of interest are determined indirectly through

administrative databases such as cancer registries or vital statistics databases.

Individuals who do not appear in these databases are assumed to remain free

of the event and at continuing risk of developing the event. This assumption can

be invalid if individual(s) have left the population at risk through migration to

regions or countries not covered by databases being used to monitor the events

of interest [1, 8]. Out-migration represents a special type of loss to follow-up in

many CRL studies and is often ignored due to a lack of ability to characterize

the impact of the loss on study results.

It is well recognized that loss to follow-up in cohort studies is problematic

since it can lead to biases in the risk estimation [9-13] . In the case of out-

migration in CRL studies, loss to follow-up would lead to under-counting of the

numerator (number of events of interest) and over-counting of the person-years

at risk. When comparing to external cancer rates, losses result in artifactually

reduced risk ratios [1, 8].

For within cohort comparisons (e.g., using Poisson regression), the impact

of out-migration on the risk estimate depends on the mechanism of loss to

follow-up. Greenland [11], and more recently, Kristman and colleagues [12]

showed that no important biases were observed with levels of loss to follow-up

between 5 to 60% when the losses were missing completely at random (MCAR)

or missing at random (MAR). However, this does not hold true when the loss

occurs not at random (MNAR).

91

The current study employs CRL methodology to re-construct an

occupational cohort of uranium miners employed in Ontario in order to

investigate cancer risks associated with exposure to ionizing radiation caused by

radon decay products. Cohort members were assembled using the Work History

File and the National Dose Registry databases for the period between 1954 and

1996 and followed passively using cancer registry and death files through

December 31, 2004. Although exposure data were available at the national

level (i.e., wherever an Ontario miner worked within Canada), outcome data

(cancer incidence/mortality and fact of death) were available only provincially.

As such, the current study is susceptible to loss to follow-up due to migration of

cohort members to geographical locations outside of Ontario. If the problem of

out-migration is ignored, then computation of standardized incidence/mortality

ratios would result in reduced risk estimates. Therefore, the methodological issue

of interest in this Chapter is whether in this situation, risk estimates based on

within cohort comparisons are unbiased.

Objectives

The overall objective of this Chapter is to assess the impact of the loss to

follow-up by determining whether estimates of the relative risk of death due to

gastrointestinal cancer differed depending on whether provincial or national

outcome databases were employed for a cohort of Ontario miners employed

between 1954 and 1981. The specific objectives are as follows:

92

1. To describe the results of record linkage of the Current Study that relied

solely on Ontario mortality database to identify deaths in comparison to

those of the earlier Muller Study [14] that had used the Canadian

(national) mortality database to identify deaths for the same cohort;

2. To derive and compare the relative risks of gastrointestinal, lung, and all

cancers deaths from the Current Study to those based on the Combine

Linkage (cancer deaths identified from Current Study and deaths found in

the Muller Study that were not found in the Current Study) scenario;

Methodology

Overview

Muller and colleagues linked the Ontario uranium miners cohort to the

Canadian Mortality Database (CMDB) on two occasions, in 1977 and 1981 [14,

15]. The results (deaths) from the most recent linkage (1981) were available for

comparative analysis. Deaths identified outside of Ontario in the Muller studies

represent an estimate of the loss-to-follow-up (out-migration) of cohort members

of the Current Study.

The Current linkage was conducted completely independent of the

Muller linkages. Considering the results of the Muller study together with those of

the Current Linkage (i.e., deaths identified within Ontario), a combined mortality

data file was created representing a “Combine Linkage” of the same cohort

93

with cancer deaths identified from both linkages. Specifically, the two groups

are defined as follows:

• Current Study = Deaths from Current Linkage (i.e., restricted to

Ontario outcomes files)

• Combine Linkage =Deaths from Current Linkage + Deaths from

Muller Linkage not found by the Current Study

Deaths occurring outside of Canada would not be captured by either

linkage so their impact could not be evaluated; the number of such deaths is

expected to be relatively small. To characterize the impact of loss-to-follow-up,

changes in the proportion of deaths and relative risk (and 95% confidence

intervals, CI) between the Current Study and the Complete Linkage were

computed.

Definition of Mechanisms of Loss to Follow-up

Missing data are commonly classified in one of three categories based on

the mechanism of the loss: i) missing completely at random (MCAR), ii) missing at

random (MAR), and iii) missing not at random (MNAR) [12, 16]. Specifically,

these are defined as follows:

Missing Completely At Random (MCAR) occurs when the probability

that a subject remains in the study is not related to the exposure or

disease status. The remaining sample in the cohort therefore may be

considered to be a random subsample of the original cohort.

94

Missing At Random (MAR) occurs when the probability of the subject

remaining in the study is related to the exposure and confounders but

not to the outcome of interest.

Missing Not At Random (MNAR) occurs when the probability of loss

relates directly to the outcome of interest and cannot be completely

explained by the other covariates. The probability of loss may also be

related to exposure status and should not be ignored in the analysis

due to possible biases in risk estimation.

The relationship between mechanism of loss and the impact on risk

estimates has been demonstrated by Greenland [11] and Kristman [12] . Both

simulation studies showed that if the proportions of loss are constant across

exposure strata, then the resulting risk estimates are unbiased. However, if these

proportions are not constant with respect to the exposures, the resulting risk

estimates would be biased. The extent of the bias depends on the magnitude

and direction of the loss.

Algebraically, Kristman and colleagues have shown (Figure 1a to 1c were

reproduced from Kristman et al. 2004 [12]) that if the loss is equally distributed

across exposure groups (i.e., MCAR, Figure 1b), then the magnitude of the odds

ratio (OR), an estimate of the relative risk, is the same as in a theoretical

complete cohort with no loss to follow-up. Similarly, it can be shown that when

the loss follows the MAR mechanism (Figure 1c) then the loss occurred

95

proportionally to the exposure groups and the magnitude of the risk estimate

remains the same as the original cohort.

The situation in the Current Study is shown in Figure 1d where some

outcomes (deaths) are missing, in particular deaths that occurred outside

Ontario as identified in the Muller linkage. In this scenario, following Kristman and

colleague’s rationale [12], it can also be shown algebraically (Figure 1d) that an

unbiased risk estimate will be obtained if the loss of the deaths occurs in the

same proportion in the exposed group as in the non-exposed group (i.e.,

proportionally constant). In this case the magnitude of the risk estimate would

be the same as that for the complete cohort.

Data Sources

Two data sources were used in this analysis:

i) Current Study linkage deaths to December 31 2004, and,

ii) Muller linkage deaths up to 1981.

The Current Study contained the unique mining certificate number

(‘mcert’), date of birth, year of death, cancer death (by cancer types), and

fact of death coded to ICD-9. Cancer deaths were determined by

computerized record linkage to the Ontario Mortality Database.

The Muller death file also contained information on cause of death (ICD-

9), date of death, and place of death for those uranium miners who died up to

1981. Vital status in the Muller study was determined by record linkage to the

Canadian Mortality Database. The Muller death file also contained the same

96

unique mining certificate number (‘mcert’) that enabled merging with the

Current Study file to create the Combined Linkage file.

Study population

The study population consisted of men who worked in uranium mines in

Ontario between 1954 and 1981. Miners who started work after December 31,

1981 were not included in this analysis. Miners who started work before 1981 and

died after December 31, 1981 were considered to be alive as of December 31,

1981.

Study Period

Although the Current Study extended the period of follow-up to

December 31, 2004, this analysis (Chapter 3) was restricted to a comparison up

to 1981 to match the study period used for the Muller analysis. Therefore, in this

Chapter, the study period is 1954-1981.

Outcomes of Interest

The primary cancer causes of deaths of interest were: i) esophageal

cancer (ICD-9: 150), ii) stomach cancer (ICD-9: 151), and iii) colorectal cancer

(ICD-9: 153, 154). Due to the small sample size of the first 2 cancer causes of

death, lung cancer (ICD-9: 162) and all cancer causes of death (ICD-9: 140-208)

were also examined.

97

Figure 7: Algebraic illustration of the impact of loss to follow-up on the odds ratio

for the complete cohort, missing completely at random, and missing of case

group in the Current Study.

Figure 1a. Complete Cohort (no loss to follow-

up)

Case Non-case Total Exposed pn* (1-p)n n Non-exp pn (1-p)n n

Total 2pn 2n-2pn 2n

The OR for a theoretical

complete cohort (with no loss to

follow-up) is equal to 1.0.

Odds ratio = OR = pn(1-p)n / pn(1-p)n = 1.0

Figure 1b. Missing Completely At Random

(MCAR) Case Non-case Total Exposed rpn r(1-p)n rn Non-exp rpn r(1-p)n rn

Total 2rpn 2rn-2rpn 2rn

Although the cohort is not

complete, the proportion of

missing subjects is equally

distributed throughout the cell. In

the case of MCAR, the OR

remains at 1.0.

Odds ratio = OR = rpn(1-p)nr / rpn(1-p)nr = 1.0.

Figure 1c. Missing At Random (MAR) Case Non-case Total Exposed rpn r(1-p)n rn

Non-exp pn (1-p)n n

Total rpn+pn n-np+rn-

rnp

n(r+1)

Odds ratio = OR = rpn(1-p)n / rpn(1-p)r = 1.0.

In the case of MAR, the loss

occurred proportionally in the

exposed group. Despite the loss,

the risk estimate remained the

same as the complete cohort at

1.0.

Figure 1d. Misclassification of disease status Case Non-case Total Exposed pn+x (1-p)n-x n Non-exp pn+x (1-p)n-x n

Total 2pn+2x 2n-2pn-2x 2n

Cu

rre

nt

Stu

dy

Odds ratio = OR = (Pn+x )(1-p)n-x / (Pn+x )(1-p)n-x =

1.0.

Given that only death file is

available from the Muller

linkage, only missing cases are

added to the case group. If the

proportion of missing is the same

in the exposure categories within

the case group, then the OR

remains unchanged at 1.0.

Note: *p-proportion of subjects with the outcome; n-number of subjects; r-proportion of subjects

remaining in the cell. (Figure 1a to 1c adopted from Kristman et al 2004 [12])

98

Exposures of Interest

Exposure variables of interest were cumulative radon exposure, and

duration of employment. The median value was used to create a binary

variable (exposed and non-exposed). A binary rather than multi-category was

used to ensure adequate number of deaths in each category. Table 1

summarizes the cut-points used to generate the binary values for the respective

exposure variables needed for the 2x2 table.

Table 17: Exposure variables of interest and median cut-points used to create

dichotomous exposure groups.

Statistical Analysis

Part 1 of this Chapter used descriptive statistics to compare results from

the Current Study where outcome information was determined using provincial

outcome databases with results of the Muller Study where outcomes were

determined using national databases. The difference represent estimated loss to

follow-up for the current study.

Exposure Status for 2x2 Contingency Table

Exposure Variable Median

Exposed Non-

exposed

Cumulative radon (WLM) 7.39 WLM > 7.39 WLM <=7.39

WLM

Duration of Employment 3.00 years > 3.00 years <= 3.00

years

99

Part 2 of this Chapter aims to determine the mechanism of loss, relative risk

estimates and 95% confidence intervals. The relative risks were estimated for the

Current Study linkage as well as for the Combine Linkage where Current Study

results were ‘supplemented’ with those from the Muller linkage. The Combined

Linkage represents the ‘Gold Standard’ since it contains deaths that were

missed by the Current Study as well as deaths that were missed in the Muller

Study.

For the relative risks, 2x2 contingency tables (Table 2) were calculated for

column 1 risks as follows [17]:

Table 18: Theoretical 2x2 contingency table

The column 1 relative risk (RR1) is defined as risk of row 1 relative to row 2 and

was calculated as follows:

Column 1 Column 2 Total

Row 1 n11 n12 n1 ·

Row 2 n21 n22 n2 ·

Total n·1 n·2 n

)1(.2

212|1

.1

111|1

2|1

1|11 n

npand

n

npwhere

p

pRR ===

100

The 95% confidence limits for RR1 are:

where

and Z is the 100(1 - α/2) percentile of the standard normal distribution.

)2()exp(*),exp(* 11 vZRRvZRR −

)3(11

)(lnvar21

2|1

11

1|11 n

p

n

pRRv

−+

−==

101

Results

Part 1: Comparison of Current and Muller Record Linkage Results

Table 3 provides summary characteristics for the 25,834 cohort members

who were ever employed in an Ontario uranium mine between 1954 and 1981.

The median age at which these miners started uranium mining was 23 years.

Over this period, on average they accumulated 24 WLM of radon exposure,

however, the variability in exposure is quite large, ranging from zero (non-

detectable) to almost 400 WLM. The majority of miners worked only for a short

period of time, the median duration of employment being less 3 years, with the

mean being 4.2 (SD 4.1) years.

Table 4 shows the number of deaths for all cancer causes of deaths as

well as deaths due to cancers of the esophagus, stomach, colorectal, lung

cancer, as well as non-cancer deaths. Between 1954 and 1981, the Current

Study identified 297 cancer deaths compared to 415 cancer deaths identified in

the Muller Study. The same number of deaths due to esophageal cancer was

identified in both studies. However, 11 more deaths due to stomach cancer and

10 more deaths due to colorectal cancer were identified in the Muller study as

compared to the current study. In total, 1,227 deaths were identified in the

Current Study based on the provincial linkage, while Muller’s linkage to the

Canadian Mortality Database yielded 1,947 deaths, a difference of 720 deaths.

102

The Combine Linkage of the two studies provided 2,097 deaths at the end of

follow-up in 1981.

Table 19: Employment Characteristics of the Ontario cohort of uranium miners

(1954-1981)

First employed as an Ontario

uranium miner

1954-1981


Cumulative exposure to Radon* (n) 25,556

Mean (SD) 23.9 (44.46)

Range 0-399

Median

Missing (n)

7.38

278

Duration of employment (n) 25,766

Mean (SD) 4.2 (4.1)

Range 0-33

Median

Missing

3.0

68

Note: * Radon daughters measured in Working Level Months (WLM); SD-

Standard Deviation

103

Table 20: Summary of number of deaths found in the Current Study, Muller study,

and Combined Linkage (both Current and Muller linkages (1954-1981))

Table 5 compares the number of cancer deaths detected by the Current

Study and those of the national linkage conducted by Muller by year of death.

The absolute and proportional differences in the number of deaths detected

were much larger for earlier years than more recent years. For example,

between 1954 and 1963, the Current Study found 17 deaths compared to 29

cancer deaths found in the Muller linkage, a difference of 12 cases or 71% more

deaths detected in the Muller study. Differences were larger in earlier years than

in later years. Overall, for the comparison period between 1954 and 1981, there

were 40% more cancer deaths identified in the Muller linkage using national

Cause of Death (ICD-9)

Current Study (n)

Muller 1981 (n)

Combine Linkage (n)

All Cancer Causes

(140-208)

297 415 438

Esophageal (150) 4 4 6

Stomach (151) 22 33 33

Colorectal (153,

154)*

30 40 40

Lung (162) 144 172 209

Non-cancer 930 1310

1424

Total 1,227 1,947 2,097 Note: *ICD-9 159.0 was not used to be consistent with Muller study Colorectal = 153 and

154 only); ** One death had missing code, assumed to be death due to non-cancer

causes.

104

data sources compared to the current linkage conducted using provincial data

sources.

Table 21: Comparison of number of cancer death found in the Current study

and Muller linkage based on the number of cases (all cancer causes) of death

between Current and Muller Study (1954-1981).

Figure 2 shows the frequencies of cancer deaths by calendar year for deaths

between 1954 and 1981 for both the Current Study (black bars) and the Muller

linkage (white bars). In both linkages, the number of deaths increased as the

years progressed. As the miners aged, deaths due to cancer became more

frequent. In every calendar year, there were more deaths found in the Muller

study than in the Current Study.

Period Current (A) Muller (B)Absolute Difference

(B-A)Proportion

((B-A)/ A)(%)

1954-1963 17 29 12 711964-1968 32 49 17 531969-1973 54 79 25 461974-1978 100 140 40 401979-1981 94 118 24 26

Total 297 415 118 40

105

Figure 8: Comparison of numbers of cancer deaths for the Current Linkage to

Muller linkage (1954-1981) by year of death.

0102030405060

1954

1955

1956

1957

1958

1959

1960

1961

1962

1963

1964

1965

1966

1967

1968

1969

1970

1971

1972

1973

1974

1975

1976

1977

1978

1979

1980

1981

Curr

ent (

n)0

00

01

32

43

45

010

107

314

1212

1326

1916

1821

2440

30

Mul

ler (

n)0

00

21

44

66

66

413

1511

1115

1718

1835

2524

3125

3050

38

Number of Deaths (All Cancers)

Year

of D

eath

106

Table 6 depicts a cross-tabulation of the linkage results of the Current

Study with the Muller Study for all cancer deaths and demonstrates that neither

linkage was perfect. There were 23 Ontario cancer deaths identified in the

Current Study that were not identified in the Muller Study. Conversely, there were

141 cancer deaths found in the Muller linkage that were not identified in the

Current Study. In the two studies combined (i.e., Combine Linkage), a total of

438 died of cancer.

Deaths occurring outside of Ontario represent out migration of the Ontario

uranium miners cohort. Table 7 shows place of deaths for the 141 miners whose

deaths were not captured in the Current Study. Of these, 78% occurred outside

of Ontario with nearly 38% died in Quebec and another 11% died in the

neighboring province of Manitoba. Thirty-one Ontario deaths were not

detected by the Current Linkage. Even though Saskatchewan has active

uranium mining operations, only 2% of deaths were found in this province. This

suggests that employment was not the primary motivator for the out migration.

107

Table 22: Comparison of linkages of all cancer causes of deaths between

Current and Muller Study (1954-1981)

Table 23: Place of death of miners found to have died from cancer in Muller

Study but not in the Current Study (1954-1981)

Place of Death Number of

Miners Percent

Prince Edward Island 1 0.71

Nova Scotia 3 2.13

New Brunswick 2 1.42

Quebec 53 37.56

Ontario 31 21.99

Manitoba 15 10.64

Saskatchewan 3 2.13

Alberta 7 4.96

British Columbia 22 15.60

Yukon 1 0.71

Newfoundland 3 2.13

Total 141 100%

Current Study

Dead Alive Total Dead 274 141 415

Alive 23 0 23

Mu

ller

‘81

Total 297 141 438

108

Part 2: Determination of Potential Biases: Current Study vs. Combine Linkage

Figure 3 shows the relative risks for the exposed group with a cumulative

radon dose of more than 7.39 WLM compared to those with cumulative dose of

7.39 WLM or less for the Combined Linkage and the Current Study.

Results for esophageal cancer (Figure 3A) are difficult to interpret due to

random variation of small numbers.

For stomach cancer (Figure 3B) there were 22 deaths identified in the

Current Study. An additional 11 stomach cancer deaths were added from the

Muller study to form the Combined Linkage. These 11 deaths would have been

misclassified in the Current Study as being still alive at the end of follow-up.

Proportionally, there were more stomach cancer deaths missed in the non-

exposed group (42%) as compared to the exposed group (29%), a net

difference of 13% between the two groups. Since the net difference is not 0, it

suggests that the loss-to-follow up deviates away from missing at random (MAR)

shifting towards missing not at random (MNAR). The differential loss is shown in

the change in the relative risk. The confidence interval of the two risk estimates

overlaps, the RR increased from 2.14 (95%CI; 1.04-5.23) for the Current Study to

1.75 (95%; 0.86-3.55) for the Combined analysis respectively. Similar trends were

observed for colorectal cancer deaths.

For all cancers combined, the proportion of the loss in the exposed group

compared to the non-exposed group is quite similar leading to similar risk

109

estimates for the Current study (RR= 2.64, 95%; CI 2,05-3.42) and the Combine

Linkage (RR=2.45, 95%CI; 2.05-3.42).

Figure 4 shows the relative risks associated with duration of employment

for the Current Study and the Combine Linkage analyses for esophageal,

stomach, colorectal, lung, and all cancers combined. The median duration was

used to determine the exposed (>3 years) and non-exposed group (<= 3 years).

As in analyses using cumulative exposure to radon decay products, comparison

using duration of employment also suggests an overestimation of the RR in the

Current study relative to the Combine Linkage.

110

Figure 9: Comparison of changes to the unadjusted relative risks and proportions

of deaths in the exposed and non-exposed groups to radon gas (WLM) for

Combine linkage relative to the Current Study (1954-1981).

Dead Alive Total Dead Alive TotalExposed 3 12.778 12.781 Exposed 1 12.780 12.781 66,67%Non-Exp 3 12.772 12.775 Non-Exp 3 12.772 12.775 0,00%

Total 6 25.550 25.556 Total 4 25.552 25.556 ?p 66,67%


Total 33 25.523 25.556 Total 22 25.534 25.556 ?p -13,10%


Total 40 25.516 25.556 Total 30 25526 25.556 ?p -11,90%


Total 209 25.347 25.556 Total 144 25.412 25.556 ?p -18,66%


Total 438 25.118 25.556 Total 297 25.259 25.556 ?p -5,29%

RR =2.33 (95% CI: 1.19-4.59) RR = 2.75 (95% CI: 1.22-6.18)

Figure D: Death due to lung cancer (ICD-9: 162)Combine (Current + Muller deaths) Current Study

Notes: ICD-9 - International Classification of Diseases, 9th Revision; WLM - Cummulative Working Level Months; Exposed - > 7.39 WLM; Non-Exposed <= 7.39 WLM; RR - Relative Risk; CI - Confidence Interval; r-proportion of original subjects lost; ?p - change in the proportion of original subjects lost from the exposed group vs. non-exposed (Non-exp) group. Fisher´s exact p-value > 0.05.

RR =2.45 (95% CI: 2.00-3.02) RR = 2.64 (95% CI: 2.05-3.42)

RR =3.56 (95% CI: 2.57-4.96) RR =4.79 (95% CI: 3.11-7.38)

Figure E: All Cancer Mortality (ICD-9: 140-208)

Combine (Current + Muller deaths) Current Study

WL

M

Proportion (%)

Proportion (%)

Figure A: Death due to cancer of the esophagus (ICD-9: 150)

WL

M

RR = 1.00 (95% CI:0.20-4.95) RR = 0.33(95% CI:0.03-3.21)


RR = 1.75 (95% CI:0.86-3.55) RR = 2.14 (95% CI: 1.04-5.23)

Proportion (%)

Proportion (%)

WL

M

Proportion (%)Figure C: Death due to colorectal cancer (ICD-9: 153, 154)


WL

M

Figure B: Death due to stomach (ICD-9: 151)Combine (Current + Muller deaths) Current Study

WL

M

111

Figure 10: Comparison of crude relative risks and changes in proportion of

deaths in the exposed and non-exposed groups to as measure by duration of

employment for Combine Linkage and deaths identified in the Current Study

(1954-1981).


Total 6 25.760 25.766 4 25.762 25.766 ?p 25,00%


Total 33 25.733 25.766 22 25.744 25.766 ?p 5,50%


Total 40 25.726 25.766 30 25736 25.766 ?p -20,00%


Total 209 25557 25.766 124 25622 25.746 ?p 3,94%


Total 438 25328 25.766 297 25469 25.766 ?p -7,29%

Dur

(Yrs

)

RR =1.47 (95% CI: 0.79-2.71) RR = 1.91 (95% CI: 0.93-3.93 )

Figure D: Death due to lung cancer (ICD-9: 162)Combine (Current + Muller deaths) Current Study

Notes: ICD-9 - International Classification of Diseases, 9th Revision; Exposed - > 3.00 years, Non-Exposed - <3.00 years; RR - Relative Risk; CI - Confidence Interval; r-proportion of original subjects lost; ?p - change in the proportion of original subjects lost from the exposed group vs. non-exposed (Non-exp) group; Fisher´s exact p-value > 0.05.

RR =1.32 (95% CI: 1.10-1.60 RR = 1.47 (95% CI: 1.17-1.85)

RR =1.72 (95% CI: 1.31-2.67) RR = 2.10 (95% CI: 1.51-2.95 )

Figure E: All Cancer Mortality (ICD-9: 140-208)Combine (Current + Muller deaths) Current Study

Dur

(Yrs

)

Proportion (%)

Proportion (%)

Figure A: Death due to cancer of the esophagus (ICD-9: 150)Combine (Current + Muller deaths) Current Study

Dur

(Yrs

)

RR = 0.73(95% CI:0.13-3.98) RR = 0.49 (95% CI:0.05-4.67)

RR = 0.47 (95% CI:0.21-1.03) RR = 0.43 (95% CI: 0.16-1.16)

Proportion (%)

Proportion (%)

Dur

(Yrs

)

Proportion (%)Figure C: Death due to colorectal cancer (ICD-9: 153, 154)


Figure B: Death due to stomach (ICD-9: 151)Combine (Current + Muller deaths) Current Study

Dur

(Yrs

)

112

Discussion

Results from this chapter indicate that approximately 40% of deaths were

missed by the Current Study. The loss occurred more frequently in earlier years

than in recent years. Overall, the missed deaths appear to be occurring not at

random (MNAR). Proportionally, more deaths were lost in the non-exposed

group than the exposed group. As a result, the estimate of the relative risks was

modestly higher in the Current Study as compared to the Complete Linkage.

The high loss to follow-up was somewhat surprising for the following

reasons:

• A long latency of exposure and disease relationship makes it unlikely that

workers selectively leave Ontario based on disease status;

• Duration of employment was relatively short, making decision about

leaving Ontario due to mining experiences unlikely; and,

• Miners were not informed about their exposure levels; therefore, it is

unlikely that differential loss occurred due to knowledge about exposure

levels.

Given the high lost to follow-up, a number of options were examined that

could potentially minimize any potential biases; however, none were particularly

effective due to limited statistical power to detect an association. These options

included the following:

• Examine only miners who started work after 1968 where the proportion of

loss appeared to be smaller;

113

• Restrict analysis to those born in Ontario;

While loss to follow-up is a methodological challenge that is frequently

acknowledged in cohort studies, its impact on the risk estimates are rarely

quantified in practice, likely due to the lack of data to determine the extend of

the loss. While the loss to follow-up in this study is high, similar losses have been

observed in other uranium miners cohorts. For example, Radium Hill cohort in

Australia experienced a loss of 36% [18] . Like the Australians, higher proportions

of the loss to follow up occurred in the lower exposure group. The German

uranium miners cohort had also indicated significant losses to follow-up. Kreuzer

and colleagues [19] used a ‘correction’ factor to inflate the number of

detected deaths to account for undetected deaths. However, this would

require assumptions about disease rate and registry error rate. Since both of

these factors have changed over time, making such assumptions would

introduce additional sources of uncertainty.

While the loss to follow-up suggests a bias in this study, the absolute

difference in the risk estimate of the Current Study compared to the Combine

Linkage is modest. For example, when comparing the risk estimates for

cumulative dose of radon decay products (Figure 3c), the Current Study

provided a risk estimate of 2.75 (95%CI; 1.22-6.18) compared to 2.33 in the

Complete linkage (95%CI; 1.19-4.59), a risk difference of only 0.42 with the

confidence interval overlapping. The differences are even smaller for the all

cancer deaths analysis (Figure 3e). For the Current Study, the risk estimate was

114

2.64 (95% CI; 2.05-3.42) compared to the risk estimate for the Combined Linkage

of 2.45 (95%CI; 2.00-3.02) representing a risk difference of only 0.19 with almost

identical confidence intervals.

Conclusion

Results from this Chapter confirm that loss to follow-up did occur. The loss

was greatest in earlier years than in more recent years. Overall, there was a 40%

loss to follow up when linking the Ontario Uranium Miners Cohort to the

provincial rather than national outcome databases. The results also indicate

that the loss occurred more frequently in the lower exposed group suggesting a

loss occurring not at random. As a result, risk estimates in the Currently Linkage

are modestly overestimated.

115


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Ottawa,. p. 13-21.

3. Newcombe, H.B., et al., Automatic linkage of vital records. Science, 1959. 130: p.

954-9.

4. Smith, M.E., The present state of automated follow-up in Canada--Part I:

methodology and files. J Clin Comput, 1980. 9(2): p. 1-18.

5. Smith, M.E. and H.B. Newcombe, Automated follow-up facilities in Canada for

monitoring delayed health effects. Am J Public Health, 1980. 70(12): p. 1261-8.

6. Smith, M.E. and H.B. Newcombe, Use of the Canadian Mortality Data Base for

epidemiological follow-up. Can J Public Health, 1982. 73(1): p. 39-46.

7. Smith, M.E., J. Silins, and J.P. Lindsay, The present state of automated follow-up

in Canada--Part II: the products. J Clin Comput, 1980. 9(2): p. 19-30.



9. Altman, D.G. and J.M. Bland, Missing data. Bmj, 2007. 334(7590): p. 424.

10. Burton, A. and D.G. Altman, Missing covariate data within cancer prognostic

studies: a review of current reporting and proposed guidelines. Br J Cancer,

2004. 91(1): p. 4-8.

11. Greenland, S., Response and follow-up bias in cohort studies. Am J Epidemiol,

1977. 106(3): p. 184-7.

116

12. Kristman, V., M. Manno, and P. Cote, Loss to follow-up in cohort studies: how

much is too much? Eur J Epidemiol, 2004. 19(8): p. 751-60.

13. Kristman, V.L., M. Manno, and P. Cote, Methods to account for attrition in

longitudinal data: do they work? A simulation study. Eur J Epidemiol, 2005. 20(8):

p. 657-62.




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1946-53.

117

Chapter 4: Gastrointestinal Cancer Risks Associated

with Exposure to Radon Decay Products

118


Introduction....................................................................................................................123

Objectives ......................................................................................................................127

Method...........................................................................................................................128

Study Design...............................................................................................................128

Study Cohort ..............................................................................................................128

Cancer Incidence and Mortality Ascertainments ...............................................135

Study Variables ..........................................................................................................136

Hierarchy of Data Assignment.............................................................................136

Outcome Variables...............................................................................................137

Radon Exposure.....................................................................................................138

Description of Study Covariates and Derived Variables.................................139

Statistical Methods ....................................................................................................143

Data Mining............................................................................................................143

Poisson Regression Model ....................................................................................145

Linear Test for Trend...............................................................................................145

Results..............................................................................................................................147

Discussion .......................................................................................................................152

Strengths and Limitations......................................................................................152

Interpretations of Study Findings .........................................................................154

I) Esophageal Cancer...........................................................................................154

II) Stomach Cancer...............................................................................................156

III) Colorectal Cancers..........................................................................................159

IV) Lung Cancer.....................................................................................................160

V) Record Linkage.................................................................................................162

VII) Risk Modeling...................................................................................................166

VIII) Poisson Regression: Grouped vs. Ungrouped Data..................................171

Conclusions....................................................................................................................172

Chapter 4 References..................................................................................................173

Chapter 4 Tables and Figures .....................................................................................178

119

Abstract

Objectives

This objective of this Chapter is to present the results of analyses examining

the risks for diagnoses (incidence) and deaths (mortality) due to cancers of the

gastrointestinal tract (esophagus, stomach, and colorectal cancers) for a cohort

of Ontario uranium miners who have been exposed to alpha ionizing radiation,

namely, radon decay products.

Methods

The analyses were based on a dynamic cohort of men who were ever

employed as uranium miners in Ontario at anytime between 1954 and 1996. This

cohort was retrospectively constructed using data from the Work History File and

the National Dose Registry. Cohort members were followed from entry until the

event of interest (diagnosis or death due to cancer of the esophagus, stomach,

or colorectal) was observed. Otherwise, date of death from other causes or the

end of follow-up (December 31, 2004) was noted to determine the person years

at risk. For each miner, cancer status was determined by record linkage of

unique identifiers of each miner with the Ontario Cancer Registry. Fact of death

for non-cancer deaths were obtained from the Ontario Mortality Database.

Exposure to radon decay products were previously estimated and recorded in

units of Working Level Month (WLM). Internal comparisons based on the Poisson

regression technique for grouped data was used to derive the relative risks

associated with exposure to radon decay products.

120

Combined analyses (gastrointestinal cancer (GI) = esophagus, stomach,

and colorectal) were also conducted to increase statistical power. In addition,

lung cancer risks were also computed to facilitate comparison of results with

previous analyses of this cohort and other cohorts published in the literature.

Results

The final cohort consisted of 28,273 male uranium miners who were

employed in an Ontario uranium mine between 1954 and 1996. In total, these

miners contributed over 900,000 person-years of observation. For the period

between 1964 and 2004, 34 miners were diagnosed with esophageal cancer, 86

miners developed stomach cancer, and 359 miners were diagnosed with

colorectal cancer. For the period between 1954 and 2004, there were 40

deaths due to esophageal cancer, 69 from stomach cancer, and 176 from

colorectal cancer identified in the Ontario Cancer Registry. Approximately half

(51%) of the miners were first employed in the uranium mines prior to 1968. As

with other cohorts elsewhere, Ontario uranium miners only worked for a short

period of time. The median duration of employment was only 3 years. On

average, the cumulative exposure was 18.2 WLM with a wide range of 0 WLM to

1169 WLM. Miners who were employed before 1968 where ventilation was poor

experienced much higher doses of radon than those employed on or after 1968.

For example, for miners who were employed less than 2 years, the cumulative

dose experienced by miners who were first employed before 1958 was 6.62

WLM. For the same duration, miners employed after 1978 had a cumulative

121

dose of only 0.26 WLM, a 25-fold decrease in exposure for recent workers. Age

at first employment did not appear to be a significant factor in determining the

cumulative dose received.

For both cancer incidence and mortality, significant increases in cancer

risks associated with cumulative exposure to ionizing radiation were observed for

stomach and colorectal but not for esophageal cancer. When comparing the

highest cumulative exposure group (> 40 WLM) to the referent group (0 WLM),

the relative risk was 2.30 (95%CI: 1.02-5.17) and 1.56 (95%CI: 1.07-2.27) for

diagnosis of stomach and colorectal cancers respectively. For the same

comparison, significant increases in cancer deaths were also observed for

stomach (RR=2.90, 95%CI: 1.11-7.63) and colorectal cancer (RR=1.74, 95%CI:

1.01-2.99) mortality. For colorectal cancer, the increase in cancer risk with

increasing dose was significant (P trend < 0.05).

The results from this study provided suggestive evidence of modifying

effects of duration of exposure (dose rate) and years since exposure for

colorectal cancer incidence and mortality. Modifying effects of age at first

exposure was not evident. Results from the current study also support the inverse

dose rate observed in lung cancer mortality studies among uranium miners. For

example, among those with cumulative exposures of between 20 to 40 WLM,

those with duration of at most 3 years of employment were at a much lower risk

(RR= 1.31, 95% CI: 0.67-2.56) than those with more than 3 years of employment

(RR= 2.74, 95% CI: 1.12-6.69) for the same cumulative exposure. Modification by

122

duration (dose rate) was confirmed in analysis for lung cancer diagnoses and

death.

Conclusions

Analysis of the data showed statistically significant increases in diagnosis

(incidence) and mortality of stomach and colorectal cancers associated with

exposure to cumulative radon decay products. No significant increases were

observed for esophageal cancer likely due to lack of statistical power.

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Introduction

Major epidemiologic studies conducted to date examining the

associated adverse health effects on uranium miners have largely focused on

the effects of inhaled radionuclides and risk of lung cancer mortality [1-7]. While

it has been shown that direct exposure to alpha particles emitted from radon

and its short lived decay products (222radon) through ingestion also contribute a

significant burden of ionizing radiation exposure to the major organs lining the

digestive tract [8], very little attention has been given to the possibility that

ingested radionuclides may also cause damage to major organs that come into

direct contact with the high energy transfer of alpha particles emitted from

radon decay products. Of the few studies conducted to date, collective

scientific evidence appears to be suggestive of a relationship between

exposure to ionizing radiation and increased risk of cancers along the

gastrointestinal tract, particularly those of the stomach and colorectal.

However, most of these studies lack the precision needed to demonstrate a

significant increase in risk association with exposure to radon decay products.

Morrison and colleagues first examined the mortality experience of a

cohort of 1,772 Newfoundland underground fluorspar miners with high exposure

to radon progeny [9]. For stomach cancer, they were expecting 16 fatal cases

based on general male Newfoundland mortality rates but observed 22 deaths.

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Although an elevated risk ratio was observed, it was not statistically significant

(SMR = 1.35, 95% CI; 0.85-2.05) [9]. For death due to cancer of the large intestine

(n=5) and rectum (n=1) observed deaths were non-statistically lower than

expected. However, these findings might be due to random variation due to

small numbers. Although colorectal cancers have relatively good survival,

incidence was not examined. This study was recently updated to extend the

follow-up by 11 years to end of 2001 adding 6 more stomach cancer cases,

however, the increase in stomach cancer risk remained statistically non-

significant [10]. Similarly, Tomasek and colleagues examined the mortality

experience of 4,320 West Bohemian (Czech Republic) underground uranium

miners [11]. They observed significantly higher than expected deaths for all types

of cancers combined. However, none of the GI cancers assessed in this study

was statistically significant. For esophageal (SMR = 1.22, 95% CI; 0.49-2.52),

stomach (SMR = 1.05, 95% CI; 0.79-1.35), and rectal cancer (SMR = 1.04, 95% CI;

0.67-1.55), the ratio of observed to expected were higher but not statistically

significant [11]. Laurier and colleagues examined the mortality experience of a

cohort of 1785 French underground uranium miners [12]. Comparing mortality

experience of cohort members employed for at least 2 years to that of the

general public. Overall, they observed 234 deaths from all causes but had only

expected 183 deaths due to cancer of all types (SMR = 1.3, 95% CI; 1.1-1.5). For

cause specific cancer deaths, lower than expected deaths were observed for

esophageal cancer (SMR = 0.7, 95% CI; 0.4-1.4) but higher than expected for

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stomach (SMR = 1.1, 95% CI; 0.5-2.0) and colorectal cancer (SMR = 1.4, 95% CI;

0.8-2.1) [12] .

To address the issue of poor statistical power of individual studies, Darby

and colleagues pooled data from 11 cohorts of miners that had been exposed

to ionizing radiation to examine cancer mortality risks other than lung

cancer[13]. Of the 11 cohorts, 4 were from Canada and accounted for almost

50% of men in the study (30,195 of 64,209 men in study). The Ontario uranium

miners’ cohort was the largest cohort included in this study followed by China

and Beaverlodge cohort in Saskatchewan. Darby and colleagues used indirect

standardization (external comparison) to derive the risk estimates [13]. In the

pooled analysis, significantly elevated risks for mortality due to stomach cancer

were observed(SMR=1.33, 95% CI; 1.16-1.52); however, the authors cautioned

that these risks might not be due to radon exposure since the increase was not

proportional to cumulative exposure of ionizing radiation. This study was also not

without its limitations. Although external comparisons have been used

extensively in the past, more recent studies have questioned the effectiveness of

indirect standardization in deriving unbiased risk estimates [14]. In occupational

epidemiological studies, internal comparison is viewed as being superior since it

can minimize biases caused by the healthy worker effect (e.g., diabetes,

cardiovascular diseases) and control for potential confounding factors

associated with the working environment [10]. Furthermore, exposure

information from one of the cohorts included in the Darby study (Beaverlodge,

126

Saskatchewan) was recently revised and found that exposure to ionizing

radiation was substantially underestimated [4]. Howe and Stager re-estimated

exposure for the Beaverlodge cohort by re-reviewing employment records with

respect to the location within the mine worked (e.g., stopings, drifting/raising,

travel ways, and shaft areas) and mine area-specific measurements. As a result,

the revised cumulative exposure demonstrated that controlling for these errors

resulted in significant increases in the risk estimate by 20% [4]. The increase in risk

estimate was attributed to the reduction in random measurement error that had

biased estimates to the null [4]. The impact of the revised exposure estimates of

the Beaverlodge cohort on the pooled analysis is not known. Finally, there is

significant heterogeneity in the studies that were pooled in terms of the level of

exposure experienced by miners in different cohorts. For example, because of

the low uranium ore grade in Ontario, miners employed in Ontario were typically

exposed to significantly lower doses than other cohorts such as the Colorado

miners that were also pooled in the study. While cancer risk at high doses is

better established, risks associated at low doses remain a topic of much debate

[15, 16].

In Ontario, over 28,000 men were employed to extract uranium from deep

underground mines beginning in 1954. As in the aforementioned studies,

gastrointestinal cancer risks have been previously examined [17, 18], however,

non-statistically significant risk estimates were observed at the last update in

1981. The long follow-up of this cohort of uranium miners provides a unique

127

opportunity to contribute to the current body of knowledge regarding the

relationship between exposure to ionizing radiation and risk of gastrointestinal

cancers. Ingestion of high energy alpha particles emitted from radon decay

products provides a direct route of exposure and forms a biologically-based

hypothesis of a potential relationship between exposure to ionizing radiation

and carcinogenic development of the major organs lining the gastro-intestinal

tract.

Objectives

The overall aim of this study is to assess the risk of gastrointestinal

cancer among male workers employed in Ontario uranium mines between 1954

and 1996 and who were followed until the end of 2004. Within this cohort, the

specific objectives of this study are as follows:

1. To determine whether the risk of diagnosis (incidence) of or death

(mortality) from gastrointestinal cancers (esophageal, stomach, and

colorectal) is associated with cumulative exposures to radon decay

products; and,

2. To determine whether the duration of exposure (dose rate), years since

last exposure, and age at first exposure modify these associations.

128

Method

Study Design

This study uses a retrospective cohort design of male uranium miners who

worked in Ontario between 1954 and 1996. The cohort was followed passively

until December 31, 2004. Their cancer status was monitored until December 31,

2004. Once entered into the cohort, the men were considered to be at risk of

developing the event of interest (diagnosis of or death from cancers of the

esophagus, stomach, or colorectal), or death from non-cancer causes, or end

of follow-up, which ever occurred first. Individual exposure to radon decay

products was estimated based on different methodologies that have evolved

over the years (Please refer to Chapter 2 for detailed discussion of radon

exposure assignment). The completeness and accuracy of these measurements

were closely scrutinized and have been used in previous epidemiological

investigations [17-20].

Study Cohort

The Ontario Uranium Miners (OUM) cohort was created by linkage of the

Work History File (WHF) and the National Dose Registry (NDR). Both of these data

sources contained personal information about the miner (e.g., names, date of

birth), their work history (e.g., date of employment), and their exposure

information (e.g., radon decay products).

129

The WHF is a provincial (Ontario) database containing information on all

miners of all ore types (e.g., gold, copper, nickel etc) employed in Ontario up to

1986. Male miners with at least 2 weeks of uranium mining history were extracted

from the full database for analysis in this study. In total, information on 26,367

miners with a history of uranium mining was extracted for analysis from the WHF

(See also Chapter 2 for more details on inclusion criteria). The WHF was

terminated in 1986 and therefore, information for miners who worked (or started

after 1986) were not captured in the WHF.

The second database used to create the cohort was the National Dose

Registry (NDR). The NDR is a centralized national database which monitors

ionizing radiation doses of over 500,000 radiation workers in Canada [21]

including those employed in the uranium mining industry from 1954 until the

present day. Thus, although uranium mining ceased in Ontario in 1996,

exposures of miners employed post-closure (for decommissioning, or other

occupations with radiation exposure) are still being collated by the NDR. In

addition, the NDR being national in scope includes exposures to ionizing

radiation for those Ontario miners who have also worked elsewhere in Canada.

Any worker in the NDR who has ever worked as a uranium miner in Ontario was

considered potentially eligible for cohort membership (see also Chapter 2 for

more details on inclusion criteria). In total, 210,791 employment records for

29,865 miners for the period of up to 2004 were extracted from the NDR for

analysis. Table 1 shows the distribution by province of the employment records

130

for these miners. As expected, most of the employment records were for work

conducted in Ontario (96%); however, 4% of the records were for work

conducted by the same miners in Saskatchewan.

Table 24: Distribution of employment records according to provinces and

territories of employment in Canada from 29,912 miners identified from the

National Dose Registry.

Using both the WHF and NDR, 30,914 uranium miners were identified. There

were 1,049 miners (3%) that were found in the WHF but not in the NDR.

Conversely, there were 4,594 miners that were in the NDR but not in the WHF. The

higher proportion of miners in the NDR is expected since it includes workers

employed after the WHF was terminated in 1986.

Of the 30,914 miners identified from the WHF and NDR, not all were

included in the analysis. Six exclusion criteria were applied to the entire cohort

Province or Territory

Newfoundland 24 (0.01)Prince Edward Island 1 (0)Nova Scotia 40 (0.02)New Brunswick 167 (0.08)Quebec 82 (0.04)Ontario 201,851 (95.76)Manitoba 20 (0.01)Saskatchewan 7,849 (3.72)Alberta 318 (0.15)British Columbia 51 (0.02)Northwest Territories 358 (0.17)Yukon 30 (0.01)

Total 210,791

Number of employment records (% of total)

131

as described in Table 2. Women (n=486, 1.6%) were excluded from analysis since

their small numbers would have limited any statistical inferences based on sex.

Miners with missing dates of birth were also excluded since date of birth is

required for appropriate allocation of person-years at risk and to calculate

derived variables such as age at first employment. Similarly, those with

inappropriate age at first employment were excluded. Miners under the age of

16 were excluded since they were likely too young to be employed as

underground uranium miners. Miners who were identified from the NDR with

employment history containing ‘spanner records’ were also excluded. Spanner

records were used by the NDR to assign known doses of radon to miners without

known dates of exposure. For example, a spanner of ‘190096’ indicates that the

exposure occurred anywhere between 1900 and 1996. Without specific dates of

exposure, derived variables such as duration of exposure cannot be calculated.

More importantly, date of entry into the cohort could not be established with

certainty. Miners identified from the NDR without at least one record indicating

job classification as a uranium miner (i.e., job code 601 or 610) were also

excluded to ensure that the worker was in fact at one point a uranium miner.

Finally, miners with invalid entries (e.g., exit date occurred before entry date)

were also excluded.

Figure 1 describes the exclusion process and the number of miners that

remained after the exclusion criteria were applied in sequence. In total, 2,661

miners were excluded from analysis, including 15 incidence cases and 7 deaths

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due to cancer of the esophagus, stomach, or colorectal (Table 3). Following

exclusion, analysis was performed to explore the effect of radon decay

products for 28,273 Ontario uranium miners.

133

Table 25: Exclusion criteria applied to the Ontario Uranium Miners cohort, 1954-

2004.

Exclusion Criteria Rationale for Exclusion

• Women • Less than 1% of uranium miners were

women, therefore, insufficient statistical

power to detect any cancer effects for

female uranium miners.

• Missing date of birth • This information was needed to calculate

age (e.g., age at first employment) as a

potential confounder and person-years

• Spanner records • Spanner records were used by the NDR to

assign doses of radon to miners without

known dates of exposure. Without specific

dates of exposure, derived variables such as

duration of exposure cannot be calculated.

• Invalid age at first

employment

(<= 15)

• If calculated age at first employment

(based on Date of birth and date at first

employment) was less than or equal to 15

years, the miner was excluded. This criterion

has been used previously by Howe and

colleagues [2, 3].

• Earliest date of

employment > 1996

• Since the last mine operated in Ontario was

1996 (Stanleigh Mines), therefore, individuals

who started work after 1996 were not likely

to be true uranium miners.

• Not having at least

one record as a

uranium mining

• To ensure that the miner was indeed a

uranium miner

• Invalid entry and exit

dates

• Example of an invalid entry and exit dates

includes exit date occurring before entry

date

134

Figure 11: Summary of exclusion criteria.

Exclusion Criteria

Exclude females/unknown/

missing information on sex:

(Females: n = 486)

Master Analysis File(n= 28,273)

n = 486

Remaining

n = 30,428

Master Study File

Yes No Total

Yes 25,271 1,049 26,320

No 4,594 0 4,594

29,865 1,049Total

Exclude those with missing

date of birth:

(n = 1,142)

n = 1,142

Remaining

n = 29,286

Exclude those who’s start date is

after December 31, 1996 after the

last uranium mine in Ontario

Closed

(n= 59)

n = 59

Remaining

n = 28,910

Exclude invalid age

(e.g., <= 15 yrs at first

employment)

(n = 43)

n = 376

Remaining

n = 28,851

Delete NDR “Spanner Records”

(n = 467)

n = 133

Remaining

n = 28,718

Exclude those without at least

one uranium mining record in

work history

(n = 445)

n = 445

135

Table 26: Summary of cases and deaths lost after applying the exclusion criteria.

Incidence Cases (n) Deaths (n) Cancer Site (ICD-9) Pre-

exclusion

Post-

exclusion

Total

Excluded

Pre-

exclusion

Post-

exclusion

Total

Excluded

Esophagus (150)

36 34 2 42 40 2

Stomach (151)

90 86 4 71 69 2

Colorectal (153,154,159.0) 368 359 9 179 176 3

Cancer Incidence and Mortality Ascertainments

The cohort was linked to the Ontario Cancer Registry (OCR) following

death clearance up to December 31, 2004 to identify diagnosis and deaths due

cancer. The OCR is managed by Cancer Care Ontario and at the time of this

linkage, it held data on all deaths in Ontario due to all malignant cancers (all

sites except for non-melanoma skin cancer) for the period between 1950 and

2004. For incidence, cancer diagnosis is available for the period between 1964

and 2004. The quality and completeness of the OCR for coverage of Ontario

cases was previously examined and found to be of good quality and

comparable to leading cancer registries worldwide. More detailed information

about the OCR is available in a recent IARC monograph [22]. Cases and death

occurring outside of Ontario cannot be detected and therefore miners not

known to have died in Ontario were assumed to be alive until end of follow-up.

136

In addition to cancer death and diagnosis data, the OCR also has data on all

non-cancer causes of death (fact of death) beginning 1964. Dates of non-

cancer deaths for cohort members were also extracted to conduct person-

years allocation.

All linkages used a combination of deterministic and probabilistic

methodologies with AUTOMATCH computer software. Linkages were

conducted by a researcher at Cancer Care Ontario (N. Chong) who was

blinded to exposure status of cohort members. The current linkage was

conducted blinded from any of the previous Muller linkages. Details of the

mechanism and results of the linkages are discussed in Chapter 2.

Study Variables

Hierarchy of Data Assignment

Work history and exposure information on uranium miners were obtained

from two different data sources: NDR and WHF. These two data sources at times

overlap (e.g., WLM estimates for a given year) and agreement between these

two data sources is not always perfect, creating discrepant information

regarding work history and exposure information for a given miner. It was

therefore decided a priori that NDR data prevailed since it was the most up to

date and complete data source.

137

Outcome Variables

The primary outcome variables in this study are diagnosis (incidence) of or

death (mortality) from cancers of the esophagus, stomach, and colorectal

cancers among Ontario uranium miners.

Analysis of incidence data was restricted to first primary diagnosis of

cancer. Secondary and subsequent diagnoses of cancer were not considered.

Less than 10 percent of miners had multiple cancer diagnoses (multiple

primaries). Two approaches could have been taken: 1) use only the first

recorded diagnosis, or 2) use any cancer diagnosis by an individual that is

primary. With the second choice, one individual can contribute to more than

one outcome. In this study, it was decided a priori that the former approach

(first option) should be taken since it eliminates any doubts about

interrelatedness of the two cancer sites.

In addition to the three individual cancer sites of primary interest, analysis

of all three sites combined was also examined to increase statistical power. Lung

cancers were also examined for external validation of analytic methodology

only and are not discussed in detail in this report. These outcomes were coded

according to the International Disease Classification (9th Revision) as follows:

• Primary Outcome Variables:

o Esophageal Cancer (ICD-9: 150);

o Stomach Cancer (ICD-9: 151); and,

o Colorectal Cancer (ICD-9: 153, 154, 159.0);

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• Secondary Outcome Variables:

o Gastrointestinal (GI) Cancers (ICD-9: 150, 151, 153, 154, 159.0); and

o Lung Cancer (ICD-9: 162).

Radon Exposure

Cumulative exposure to radon decay products measured in Working

Level Month (WLM) is the primary exposure of interest in this study. Radon doses

were calculated using data from WHF and/or NDR. Given that two databases

were used (WHF and NDR) both contained estimates of radon, discrepancies in

radon doses were expected as no data base is perfect. As such, a ‘Best

Estimates’ approach was used to resolve discrepant reported doses of the two

data sources using the following dose metric applied to each dose record:

• When a radon dose estimate is available only in the WHF, it is

considered as the “Best Estimate”;

• When a radon dose estimate is available only in the NDR, it is

considered as the “Best Estimate”; and,

• When dose is available in both the NDR and WHF, the NDR dose is

considered the “Best Estimate”.

Doses were then accumulated across years as illustrated in Table 4. In this

scenario, miner John Doe worked from 1956 to 1960. During this time, dose

records were found in both the WHF and NDR with a missing dose in the WHF in

1957 and a missing dose in the NDR in 1959. The cumulative dose based on the

arithmetic sum for Mr. Doe was 5.5 and 4.5 based on the WHF and NDR

139

respectively. Applying the algorithm above, the ‘Best Estimate’ of the

cumulative dose was 5.0 WLM.

Table 27: Example of calculation of cumulative doses based on ‘Best Estimate’

approach for a hypothetical miner employed from 1956 to 1960.

Calendar Year of Employment Data Source

1956 1957 1958 1959 1960

Cumulative Dose (WLM)

WHF 2.5 ≠ 2.0 0.5 0.5 5.5

NDR 1.5 0.5 1.5 ≠ 1.0 4.5

‘Best Estimate’ 1.5 0.5 1.5 0.5 1.0 5.0 Note: WLM – Working Level Month; WHF – Work History File; NDR-National Dose Registry; ≠ - Dose

not available

Description of Study Covariates and Derived Variables

Cumulative Dose of radon decay products is the main exposure of interest

for this study. For the descriptive statistics, cumulative radon doses were

presented as the sum of all exposure records, as illustrated above. In the

modeling, radon dose was considered as a time dependent variable with doses

accumulated for each risk set until the event of interest or end of follow-up. In

order to account for different induction and/or latency periods, cumulative

doses were lagged by 10 years. Sensitivity analyses with lagging of 0, 5, 15, and

20 years were also conducted with results summarized in Appendix V. Lagging

was achieved by excluding the doses received 0, 5, 10, 15, and 20 years

immediately prior to diagnosis or death. This concept was described in detail in

140

Chapter 2 and applied in this analysis based on the methods described in

Pearce and Checkoway [23, 24].

Cumulative exposure was categorized into four groups; the lowest with

a cumulative radon exposure of 0 WLM the others in 20 WLM increments so the

highest exposed group is greater than 40 WLM. Since health effects associated

with a given dose are not well established in relation to GI cancer, there are no

acceptable biologically-based cut-points.

Sex was used as an inclusion/exclusion criterion for this study. Females

were excluded from analysis due to small numbers of female uranium miners.

Those with unknown (n=593) and missing sex codes (n=143) were assumed to be

males and were included. This assumption was based on a random sample of

unknown/missing sex codes which were manually examined using given names

to determine whether the miner was male or female. Of those given names

examined, all were indicative of male miners (e.g., first name = John).

Calendar Year of Employment was available in both the NDR and WHF.

However, approaches used to assign exposure to a calendar year were slightly

different for each data source. For the NDR, the exposure year was defined as

the year in which monitoring of the exposure started. For example, if the

dosimeter was issued to a uranium miner in December of 1980, the dose of a

dosimeter would be included in 1980 even though the badge may have

accumulated some doses in parts of 1981. Since uranium miners are required to

report doses on a quarterly basis, such overlap was assumed to be insignificant

141

in this study. For the WHF, exposure assignment in early years was based on

employment information collected at annual chest examination clinics. Given

that these examinations did not always occur on the first day of each calendar

year, it was possible that a miner worked more than 12 months between

examinations. As such, the year of exposure has been ‘calendarized’ to

allocate appropriate months to a given year. In this study, the variables ‘yrs’ in

the WHF and ‘exposure_year’ from the NDR were taken to be the year in which

employment (exposure) had occurred.

Age at first Employment (exposure) was included in the analysis as a

potential effect modifier. It is a derived variable based on date of birth and

date of first employment. To examine the modifying effects of age at first

exposure, separate risk estimates were examined for two strata. Cut-points for

the strata was based on the median age at first employment distribution.

Duration of Employment has been identified as an important modifier of

the dose response relationship in lung cancer mortality studies of uranium miners

for several cohorts [25]. To date, the inverse dose rate has not been examined

for non-lung cancers.

Duration is a derived variable. The best data source used to do this would

have been the WHF. However, data were not available for miners employed

after 1986 in the WHF. Instead, multiple other approaches were used to derive

this variable, some with limited success. Three main approaches are described

below with the third approach used in this study.

142

1. Initially, duration was determined based on the first and last dates of

employment. However, closer investigation showed that this

approach greatly overestimated the duration of employment since

there were gaps in employment history. Results from this approach

were compared to external reports (BEIR VI) [26] and confirm that this

approach overestimates the duration of employment.

2. The second main strategy was to calculate duration using information

from the NDR (variables: from_period and to_period) for coding

dosimetry wearing periods in the NDR. Again, this did not prove to be

fruitful for a few reasons. Specific dates could not be determined

using this coding. The coding mechanism was designed to identify

quarterly reporting of dosimetry badge readings for uranium miners, as

such, the exact dates were not available in the database.

“Guestimates” (e.g., mid-point of the quarter) were attempted,

however, total duration did not agree with WHF data.

3. In the third approach, duration was determined based on the number

of radon readings for the miner. Although crude, this approach

agreed best with calculations for duration of employment conducted

in previous published reports [26, 27].

Date of entry (first employment) was determined using data from both the

NDR and WHF with NDR being the default value since its data was more

complete. If NDR date of entry was missing, then WHF values were used.

143

Date of Termination or End of Follow-up was calculated differently for

incidence and mortality analyses. For incidence analysis, miners contribute

person years until their date of diagnosis of first cancer (any site), or date of

death, or date of end of follow-up (December 31st, 2004), which ever occurred

first. Only the first primary cancer was considered. For analysis of mortality,

miners contribute person years until their date of death from any cause;

otherwise the date of end of follow-up constituted the termination date.

Statistical Methods

Data Mining

The final data set was examined for range of values and internal

consistencies between variables. Examples of consistency checking include

comparing date of birth relative to date at first employment and calculated

age at first employment to determine whether it is reasonable within a working

age range.

Missing values were also examined. One of the most common missing

values was day and month of dates (birth, first employment, and last

employment). In these situations, mid-month/year was used (i.e., 30 June).

144

Figure 12: Overview of analytical approach

Inci

dence

= T

able

13

Mort

ality

= T

able

14

Inci

dence

= T

able

15

Incidence & M

ortality

(Esophagus, Stomach, and Colorectal)

(10 year lag)

Results = Table 12

Mort

ality

= T

able

16

Inci

dence

= T

able

17

Mort

ality

= T

able

18

145

Poisson Regression Model

Poisson regression using the SAS GENMOD procedure (Version 9.1) was

used to model cancer risks as a function of covariate levels. The general form of

the Poisson regression model is:

λ /λo = exp (β1X1, β2X2, …, βkXk),

where X1, X2, …,Xk, are independent variables, λ is the incidence/mortality rate

for persons with specified values X1, X2, …,Xk, λo is the baseline

mortality/incidence rate, and β1, β2, …, βk are parameters estimated from the

data. Exponentiation of the regression coefficients provides an estimate of the

relative risk controlling for the independent variables (e.g., age at risk, period

employment).

Cross tabulations of data consisting of lung cancer deaths, person-years

of follow-up, and summary variables were entered into the regression models.

Person-years were calculated using a program adapted from that first

presented by Pearce and Checkoway and Villeneuve and Colleagues [24, 28] .

Data were cross-classified by attained age (<60, 60-<65, 65–<70,70+), calendar

period (< 1975, 1975-84, 1985–1994, 1995+), and cumulative RDP exposure (0, >0-

20, >20-40, >40 WLM).

Linear Test for Trend

The χ2 test for linear trend was used to determine the dose response

relationship between cumulative exposure to radon decay products and

146

cancer outcomes. Given that the exposure variable in this study was

categorized into four groups (0, >0-20, >20-40, and >40 WLM), the linear test for

trend was conducted by substituting the mean dose for level of each dose

category.

147

Results

The analysis was based on 28,273 male uranium miners (Table 7).

Collectively, these miners contributed 961,210 and 974,687 person-years to the

incidence and mortality analyses respectively. The average age at first

employment was 29 years; however, the age distribution is positively skewed

with the most frequent (mode) age at first employment being 21 years.

Approximately half (51%) of the miners began working in uranium mines before

1968. These workers were not employed as uranium miners for very long. Fifty-six

percent of the miners were employed for no more than 3 years (Table 9), the

average duration of employment being 5 years with a range of 0.5 to 22.5 years.

Short duration of employment is a common characteristic of uranium miners. For

example, the average duration of the Colorado Plateau uranium miners cohort

was 4 years [25].

Of the 28,273 Ontario uranium miners, 34 were diagnosed with

esophageal cancer, 86 were diagnosed with stomach cancer, and another 359

were diagnosed with colorectal cancer (Table 8). Some of these diagnoses also

resulted in death. For esophageal cancer, there were actually more deaths

(n=40) than there were diagnoses (n=34). This is due to the longer period of data

available for death (1954-2004) compared to diagnosis (1964-2004). That is,

incident cases of esophageal cancer (and all other cancers) diagnosed prior to

1964 would not be captured. The high death to diagnosis ratio also reflects the

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seriousness of esophageal cancer. In addition to esophageal cancer, 69 miners

died from stomach cancer and another 176 miners died from colorectal

cancer. Of the three cancers investigated, colorectal cancer has the best

survival as indicated by the smaller death to diagnosis ratio of 0.5 (176 deaths:

359 diagnoses).

Overall, the Ontario uranium miners were exposed to relatively lower

levels of radon decay products than other uranium miner cohorts. The

distribution is positively skewed with very few miners with a cumulative dose

above 100 WLM. The average cumulative exposure to radon decay products

was 18.2 WLM (SD 38.1). Table 10 shows the average cumulative dose for

different age groups at first employment by periods of first employment. Age at

first employment was not a major factor in accrued doses; however, period of

employment was a major contributor to accrued higher doses. For those who

began mining before 1958, the average level of exposure was between 36.5

and 47.14 WLM. While the level of cumulative radon exposure decreased

between 1958 and 1967 it still remained relative high at between 19.47 and

24.35 WLM. With the introduction of stricter ventilation regulations, the average

cumulative radon dose decreased to below 5 WLM for those miners who began

mining in 1978 or later. Similarly, Table 11 shows the relationship between

cumulative dose across age at first employment and duration of employment.

As expected, cumulative dose increases with increasing duration.

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Table 12 examines the average cumulative exposure to radon decay

products taking into account year of first employment and duration of

employment. For a given duration of employment, level of exposure was

dependent on the year the miner was first employed. For example, those miners

who worked for 2 to 3 years before 1958 had an average cumulative dose of

19.95 WLM. Those miners who worked for the same duration, but started in 1978

or later, have an average cumulative exposure of only 1.19 WLM.

Cancer Incidence and Mortality

Tables 13 to 19 present the main findings of the study. Adjusted risk

estimates for cancer incidence and mortality are shown in Table 13. For cancer

incidence, significant increases in risks were observed for stomach and

colorectal cancers when comparing the highest exposed group to the referent

group. Similar trends were observed for cancer mortality. Men with more than

40 WLM of cumulative exposure were 2.3 times (95% CI; 1.02-5.17) more likely to

be diagnosed with stomach cancer. Similarly, the risk of dying from stomach

cancer was also elevated with higher levels of exposure (RR=2.90, 95% CI; 1.11-

7.63). Although the risk for diagnosis or death from colorectal cancer was lower

than for stomach cancer, it was statistically elevated. Those with more than 40

WLM of cumulative exposure were 1.56 (95% CI; 1.078-2.27) and 1.74 (95% CI;

1.01-2.99) times more likely to be diagnosed with or die from colorectal cancer.

There were very few cases of esophageal cancer available for analysis, and no

significant associations were observed.

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Duration of Employment and Inverse Dose Rate

The inverse dose rate effect was observed in this study for both cancer

incidence and mortality (Tables 14 and 15 respectively). For the same

cumulative dose, higher risk estimates were observed for those with more than 3

years of employment compared to those with less than 3 years of employment.

This effect was most evident for combined gastrointestinal and lung cancer

incidence and mortality where the larger number of cases provided more

uniform risk estimation. For example, for diagnosis (incidence) of combined GI

cancers, for those with cumulative dose of more than 40 WLM, the effect

increased significantly from 0.84 (95% CI; 0.36-2.00) to 2.12 (95% CI; 1.26-3.54).

Years Since Last Exposure

The added years of follow-up allow for evaluation of the modifying effects

of years since last exposure. This was assessed by comparing the risks for those

with at most 26 years since last employment to those with more than 26 years.

Results for incidence and mortality are presented in Tables 16 and 17

respectively. Although no modifying effects were evident for esophageal and

stomach cancers, the inverse effect was observed for colorectal cancer,

combined GI cancers, and lung cancer.

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Age at First Exposure

Results from this analysis showed little evidence of a modifying effect for

risks associated with age at exposure. For example, for stomach cancer

incidence (Table 18 and 19), those who started employment at 28 years of age

or older are at almost the same risk (RR=2.43, 95% CI; 1.03-5.70) as compared to

those who began mining at a younger age (RR=2.33, 95% CI; 0.17-31.0).

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Discussion

Strengths and Limitations

This study was based on a large cohort of 28,273 uranium miners that were

followed from 1954 until 2004. Given the large cohort combined with a long

follow-up period, this study is able to investigate cancer risks associated with

exposure to radon decay products, addressing an important knowledge gap in

the literature. Of particular interest are cancers of the esophagus, stomach, and

colon-rectum since these organs come into direct contact with alpha energy

emitted from ingested radon decay products. In addition to assessing cancer

risks for mortality associated with exposure to cumulative radon levels, this study

was able to assess cancer risks associated with diagnosis (incidence), thus

addressing another important knowledge gap in the literature for radon

exposure. Furthermore, while the modifying effects of duration (dose-rate), years

since last employment, and age at first exposure have been documented in the

literature for lung cancer mortality, there is currently no literature on the effects

of these modifiers other cancer sites.

Despite these strengths, there are also some important limitations to

consider when interpreting this study’s results, in particular, the potential biases

associated with loss to follow-up (or misclassification of disease status) of a large

proportion of miners. Given that national outcome data were not available for

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this analysis, the cancer and vital status of miners included in this study were

determined by record linkage to provincial cancer registry and vital status

databases. As such, cancer and vital status of miners who have left Ontario

could not be determined. As discussed in Chapter 3, the impact of the loss to

follow-up is likely to be overestimation of relative risk. However, the degree of

overestimation could not be determined with any certainty without making

assumptions (e.g., constant error rate in cancer registration over time) that may

or may not be valid.

Calculations of radon exposure were previously conducted by mine

operators, engineers, and various regulatory bodies. As indicated in Chapter 2,

the concentration of radon daughters is measured in units of working level (WL)

which is a measure of the potential alpha particles energy per litre of air. This

represents an additional source of uncertainty in the exposure assessment in this

study since radon doses from ingestion was assumed to be proportional to

radon concentration in the air. Although the validity of this assumption needs to

be demonstrated among uranium miners, ad hoc biomonitoring of some mine

workers confirms that significant uranium significant amount of uranium had

been ingested and was ingested and excreted through the urine. While it is

conceivable that not all radon activity in air will be ingested, there is no

evidence to suggest that the amount consumed, albeit less than the

concentration found in the air, is not correlated with concentration in the air.

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Interpretations of Study Findings

Results of this study’s analyses show significant increases in incidence and

mortality associated with cumulative exposure to radon decay products for

cancers of the stomach, colorectal, and combined GI cancers. Excess risks

remained after adjustment for age and period effects. Despite extending the

period of follow up by 23 years compared to the Muller study [18], there was

limited power to characterize the risk for esophageal cancer. Comparing the

current study’s results with those of other studies is also limited to results of

mortality analyses given that cancer risks for diagnosis (incidence) has not been

addressed in other studies to date.

I) Esophageal Cancer

Very few studies to date have examined the relationship between

exposure to radon decay products and risk of esophageal cancer. This can

likely be attributed in part to esophageal cancer being a very rare type of

cancer. In Ontario, the age-standardized incidence rate for esophageal cancer

is only 6 per 10^5 [29] compared to other cancers such as colorectal which has

an ASIR of 35 per 10^5 [29]. In order to examine the radiation effects of

esophageal cancer, one would need a larger cohort with longer follow-up

periods to have sufficient power to determine associated cancer risks.

Of those who have examined the effects of radon exposure and

esophageal cancer, the results have been inconsistent. Laurier and colleagues

observed a non-significant reduction in risk of esophageal cancer (SMR=0.70,

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95%CI 0.40-1.40) among a cohort of 1,785 French uranium miners [12]. Tomasek

and colleagues found an increase in esophageal cancer among 4,320 West

Bohemia uranium miners (SMR=1.22, 95% CI 0.49-2.51) [30]. Darby and

colleagues [13] pooled and analyzed data from 11 cohorts and found an

increased cancer risk based on 45 deaths, but the risk estimate was not

statistically significant (SMR=1.04, 95% CI 0.77-1.41). More recently, a non-

significant increase was observed from the German cohort (SMR=1.10, 95% CI:

0.92-1.31) [31]. Results from the current study also show non-significant increases

in esophageal cancer risks (RR=1.51, 95%CI: 0.42-5.48) when comparing those

with cumulative exposure of more the 40 WLM to the referent group (0 WLM).

Though the magnitude is larger than that of other studies, the confidence

interval overlaps all studies published to date.

The current study results do not provide evidence of an association

between cumulative doses of radon decay products and risk of diagnosis or

death of oesophageal cancer. Although the lack of the association is in part

due to low statistical power, biological based rationale would also indicate that

this association would be unlikely. According to the ICRP GI Tract model, any

ingested radon and its decay products would not affect the oesophagus since

ingested material spend very little time at the oesophagus, not enough to

experience any significant doses from radon decay products where the half life

is 51 minutes. Other risk factors such as alcohol consumption [32], tobacco

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smoke [32], and diet [32] are likely to play a more important role in the aetiology

of oesophageal cancer than ionizing radiation from radon decay products.

II) Stomach Cancer

The current study results show significant excess stomach cancer risk for

both incidence and mortality when comparing those with cumulative exposure

to radon decay products with more than 40 WLM relative to the referent group.

These findings are consistent with those of larger studies conducted to date.

Smaller studies have shown non-statistically significant excess risks[10-12].

Among larger studies, significant excess in stomach cancer mortality has

been observed in Sweden and Germany. For example, results from the Swedish

miners showed a 45% increase in stomach cancer mortality (95% CI: 1.04-1.98)

[33]. The joint analysis of 11 cohorts showed a 33% increase in stomach cancer

mortality risk (95% CI 1.16-1.52) [13]. Results for the recently published German

study also show significant excesses in stomach cancer mortality among their

miners (SMR=1.15, 95% CI: 1.05-1.25).

All studies to date are in agreement in terms of the direction of the risks

associated with exposure to radon decay products (i.e., increased risk).

However, the magnitude of the risks appears to vary from cohort to cohort.

Differences in the magnitude of the risks may be due to the analytical strategies

applied. In previous studies, risk estimates for stomach cancer were derived by

comparing the observed versus the expected number of cases (i.e., indirect

standardization) without considering dose. In this study, internal analysis was

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used to determine the risk of stomach cancer for different cumulative doses

relative to the referent category (lowest dose group). As the difference in the

cumulative dose of radon decay products increases, the magnitude of the risk

estimates also increase.

Another factor that could also explain differences observed in the

magnitude of the risks include lagging of exposure and adjustment of potential

confounders. In some studies, no lagging of exposures immediately prior to

diagnosis were applied. The rationale being that doses incurred just prior to

diagnosis are not likely to be responsible for disease initiation. Including irrelevant

doses can ‘dilute’ the risk estimate. Differences in adjustment of confounders

can also potentially affect the size of the risk estimates. Miners are exposed to a

whole host of other agents including diesel fumes, aluminum powder, chromium

and other chemicals that could not be taken into consideration in these risk

estimates. Some of the Ontario uranium miners had a history of mining gold, and

exposure to arsenic in the gold mining process has been shown to increase

stomach mortality [34]. Sensitivity analysis was conducted to exclude miners

who had a history of gold mining. Results are presented in Appendixes VI.

Although not statistically significant, stomach cancer risks remain elevated.

Biologically, the stomach is expected to incur the highest dose from

ingested radon decay products. Based on the linear dose response relationship,

the stomach would expect to have the largest impact of all internal organs

lining the digestive tract. The current study supports this biological explanation

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where risk estimates for stomach cancer is much larger in magnitude as

compared to colorectal cancer (Chapter 4, Table 13). However, no clear dose-

response relationship was observed suggesting the increased risk was not solely

due to radon decay products.

The lack of a clear dose-response relationship suggests that other factors

that are correlated with radon exposure may also play an important role in the

aetiology of stomach cancer. Of particular interest are gamma radiation

emitted from uranium ore bodies can potentially contribute to stomach cancer

risks. Lifespan studies from atomic bomb survivors supports a linear increase in

stomach cancer risk with increasing external dose [35]. However, Cardis and

colleagues found no statistically significant trend in stomach cancer risk with

external dose nuclear workers [36].

Stomach cancer has also been shown to be associated with exposure to

arsenic in gold mining [37]. The Mining Master File contains flags to indicate

exposure to gold mining. Using these flag, sensitivity analysis was conducted to

exclude all gold miners. Although not the risk estimate remained elevated after

excluding known gold miners, the risk estimate was not statistically significant

due to low statistical power. The precision could not be improved since the MMF

was terminated in 1986 although gold mining is still being conducted in Ontario

[38].

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III) Colorectal Cancers

Comparing this study’s findings for colorectal cancer with other studies is

difficult due to inconsistencies in grouping of this cancer. For example, Tomasek

et al and Darby et al combined ICD-9: 152 (small intestine) with ICD-9: 153

(colon) together while analyzing rectum, rectosigmoid junction, and anus (ICD-

9: 154) as a separate site [11, 33]. Differences in classification may also explain

some of the heterogeneity in risk estimates. In the current study, significant

increases were observed for risks of diagnosis (incidence) and mortality due to

colorectal cancer.

Like stomach cancer, significant increases in colorectal cancer diagnosis

and deaths were associated with cumulative doses of radon decay products.

However, unlike stomach, the expected dose to the colon and rectum would

be much smaller since it is located further down the digestive tract (Chapter 1,

Table 6). Therefore, the increases in risk observed are likely to be one of a

number of reasons. Because of the large number of colorectal cancer cases,

there was sufficient statistical power to detect a smaller effect size at lower

doses. When comparing risk estimates and corresponding confidence intervals

for stomach and colorectal cancer, the risk estimates for colorectal cancer is

much smaller with greater precision (Chapter 4, Table 13). Secondly, according

to the ICRP GI Tract Model, radon decay products would spend significantly

longer period of time in the colon (~36 hours) compared to the stomach (~1

hour). Although the dose endured by the colon would be much smaller than the

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stomach, the inverse dose rate due to the longer duration would translate into a

larger impact. Finally, the increased risk might be attributed to other factors such

as exposure to gamma radiation. Since gamma radiation can penetrate to

deep inner tissues, internal organs such as the colon would just as susceptible to

exposure to gamma radiation as organs at the surface.

IV) Lung Cancer

Although not the primary focus of this study, lung cancer risks associated

with exposure to radon decay products were computed for comparison with

other studies and serves as an indirect approach of validating current study

methods. Results from the current analysis are similar to those of other studies. Of

the different cohorts, the one that is most comparable to the Ontario uranium

miners cohort in terms of Working Level (WL) is the Radium Hill Cohort from

Australia, with the average WL being 0.9 and 0.7 respectively [26]. It is

important to note that both studies had significant loss to follow-up. In the

Australian study, information for 36% of cohort members could not be traced [7].

The results of these two studies are shown in Table 5. Both studies had similar cut-

points for categories of cumulative exposure to radon decay products and the

risk estimates appear to be in agreement with each other. As expected, the

highest risk estimates were found when comparing the cumulative dose of the

highest exposed group to the referent group. In the current study, a 4-fold

increase in lung cancer mortality was observed (RR=4.22, 95% CI; 3.19-5.61) while

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the Australian study observed a 5-fold increase in risk (RR=5.2, 95% CI: 1.8-15.1).

The confidence intervals of these two studies overlap.

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Table 28: Comparison of risk estimates obtained from the current study based on

data from the Ontario Uranium Miners and the Australian study based on data

from the Radium Hill cohort.

Source

Cumulative Radon

Decay Products

(WLM)

Crude Risk

Estimate

Current Study

0

> 0 – 20

>20 – 40

> 40

-

1.89 (1.44-2.47)

2.47 (1.74-3.39)

4.22 (3.19-5.61)

Woodward et al. [7] 0

0 < 10

11 - 40

>40

-

0.9 (0.5- 1.8)

2.2 (1.0- 4.7)

5.2 (1.8-15.1)

Note: Adjusted risk estimates (and lag information) was not available for the

Australian study.

V) Record Linkage

In this study, diagnosis of and death from GI cancer as well as death from

all causes were identified by linking personal identifying information to Ontario

outcome databases. Linkage of the miner cohort with Ontario cancer

incidence and mortality files produced fewer links than expected. This

prompted further investigation of potential bias in order to assess whether these

miss-links would affect study results. In Chapter 3, risk estimates were made

based on the Current Study and that of the Complete Linkage (Current Study

supplemented with results from the national linkage). The results showed that

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missing deaths did not occur at random with more missing deaths occurring in

the lower exposed groups. However, the impact was modest with the

confidence intervals largely overlapped the two risk estimates.

Additional analyses were also conducted (not shown here) and miners who

were greater than 85 years of age (< 5%) and greater than 100 years of age (<

1%) at the end of follow up were systematically excluded. These were assumed

to be loss to follow-up given that these ages are well above the life expectancy

of the time. Excluding these individuals based on age at end of follow-up did

not affect study results. In order to adequately mitigate the problem of loss-to

follow-up (or misclassification of disease status), record linkage would need to

be conducted using national level incidence and mortality data files.

As shown in Table 7 of the results section, there were 31 cancer deaths

occurring in Ontario according to the Muller linkage but not in the Current

Study. The reasons for this are not clear and are likely due to a number of

factors. As indicated in Chapter 3, there were a number of cases that were

missed. Some of the missed cases died while living in Ontario while others died

outside of Ontario. Within Ontario, missed cases were likely a result of a number

of factors. Brenner and colleagues [39] described errors in record linkage as

being one of two types: homonym and synonym errors. Homonym errors occur

when two records from two different people are very similar and thus

erroneously assumed to be for the same person. In this study, homonym errors

are likely to be minimal given that multiple identifiers (e.g., first and last names,

164

phonetic encoding, date of birth, etc) were used. Increasing the number of

unique identifiers reduces the amount of homonym errors due to increasing the

discriminating power of the links. Synonym errors refer to errors in reporting or

coding of personal identifiers or changes in these data [39]. In this study, only

male miners were used in the analysis, therefore, surname changes due to

marriage are unlikely. Errors in coding are possible but these errors are unlikely to

be related to exposure and therefore would not bias study results.

VI) Lagging and Latency

Although it is well known that solid tumours have long latent periods

between disease initiation and detection, the exact period is not known and

largely dependent on the agent and individual characteristics. The

methodological implication is that including irrelevant exposures in the analyses

can dilute the risk estimate. A common approach taken in epidemiological

investigations are ‘trial and error’ approach by lagging the exposure in order to

discount the exposures that are thought not to relate to the etiology of the

disease [40, 41]. Rothman has argued that the lag duration resulting in the

highest risk estimate should be used since it is mostly likely to have the least

amount of non-differential misclassification [40].

Although some studies in the past have used a 5-year lag [10], such a

short latency is probably more relevant for blood cancers where the period

between initial exposure and induction is relatively short. Since solid tumours

generally require many more years between disease initiation and detection, it

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is likely that lags of more than 5-years would be more relevant for solid tumours.

Lag-years have not been consistently applied in studies conducted to date.

Most did not apply lag years while others lagged the exposure for 5-years. This

inconsistency makes it difficult to compare the current study results with previous

studies. In radiation epidemiology, the BEIR VII used a 5 year lag [42] while the

Industrial Disease Panel in Ontario used a 10 year lag in assigning exposure [43].

In this study, the main results were presented using a 10 year lag of the

exposure. This choice was based in part on examination of the magnitude of risk

estimates based on different lagging intervals (0, 10, 15, and 20 years)

summarized in Table 6. The grey shaded and bolded cells indicated the highest

risk estimates for the different cancer sites. With the exception of esophageal

cancer, where very few cases were available for analysis, the highest risk

appears to be between 10 and 15 years. For all combined GI cancers

(esophagus, stomach, colorectal cancers), the highest was based on the 10

year lag. Therefore, all risk estimates were presented in this chapter were based

on a 10 year lag.

Table 29: Magnitude of the relative risk by lag years by cancer sites

Lag years

Cancer Site 0 5 10 15 20

Esophageal Cancer * 1.08 1.13 1.51 1.82 1.91 Stomach 2.41 2.54 2.90 1.80 1.62

Colorectal 1.19 1.70 1.74 1.78 1.64

Gastrointestinal 1.33 1.77 1.95 1.80 1.66

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Lung 2.24 3.53 4.22 4.28 3.20 Notes: * Based on very few numbers of cases; Relative Risks obtained from Appendix V; Highest

risk estimate bolded and shaded in grey boxes.

VII) Risk Modeling

Although most studies published in this area use external comparison

based on indirect standardized methods (SMR) [44], this technique was not used

in the main analysis of this study. Instead the analytical strategy to estimate

cancer risks associated with exposure to radon decay products is based on the

internal comparison method, namely, the Poisson regression technique. This

approach was adopted to minimize the potential biases caused by loss to

follow-up due to out-migration of cohort members which would produce an

artifact of significantly reduced risk (See Chapter 3 on loss to follow-up).

Choice of Model

In this study, statistical models were constructed to examine the effects of radon

decay products on GI cancer risks. Two modelling approaches that could have

been used to assess cancer risk: 1) external comparison (e.g., SMR), and 2)

internal comparison (e.g., Poisson regression). Traditionally, external comparison

is used in radiation epidemiology, in part because this approach requires little

computational power to derive risk estimates. Using the external comparison

approach however has its limitations. Comparison of SMRs between studies must

be done with care since each area's population profile weights the age specific

rates are different for different populations. In addition, for some health

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conditions such as diabetes and cardiovascular diseases, the SMRs would be

prone to the healthy worker effect. When assessing cancer risks however, the

internal (within cohort) comparison is arguably a more appropriate statistical

model given that potential biases caused by the healthy worker effects are

unlikely since comparisons are made within the cohort population and not to

the general population. Furthermore, biases caused by potential confounders

(measured or otherwise) are less likely when using the internal (within cohort)

compared to the external comparison since male miners within the cohort are

expected to be more similar to each other than to males of the general

population.

Despite the many advantages of the internal comparison approach, it

too has limitations. Internal comparisons such as the Poisson regression are more

complex and require an understanding of how variables may influence or

modify cancer risk.

Confounding:

A confounding factor is correlated with both the disease under study and

the exposure of primary interest. It is a form of bias that needs to be accounted

for in the risk estimate. In this study, age at risk and period of effect are both

considered confounders and therefore are adjusted in all analyses. As with the

BEIR analyses of lung cancer risks [45], age is considered to be a confounder

since it is associated with lung mortality. Since the main exposure of interest in

the Current Study is the cumulative exposure of radon decay products, age of

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the miner also has a strong association with a total exposure since younger

workers are likely to work longer therefore accumulating more radiation

exposure [46].

Period (year of exposure) is also a strong confounder in the Current Study

since it is related to both the exposure and cancers of interest. In the early years

of mining (prior to 1968) poor ventilation practices resulted in high exposure to

radon decay products for miners. Regulatory changes implemented in later

years, however, dramatically reduced radon exposures for workers. As discussed

in Chapter 1, GI cancer trends have changed over time. For example, the

mortality rates for stomach cancer (Figure 2, Chapter 1) have decreased from

approximately 21 (per 100,000 populations) in 1964 to 6 (per 100,000

populations) in 2004.

Furthermore, period is also a proxy measure for many other factors such as

level of measurement errors. For example, before 1958 radon measurements

were not conducted in uranium mines, but rather estimates of exposure were

based on mine architecture and work conditions as determined by mine

engineers and other experts. Adjusting for period would take these errors into

consideration.

Other factors can also affect cancer risk. For example, a review of the literature

as discussed in Chapter 1 reveals that smoking, alcohol consumption, diet and

physical activity are known risk factors for GI cancers. Although the current study

does not have the data required to consider these factors, there is no evidence

169

to suggest that such factors would be strongly correlated with radiation dose,

although weak associations might arise by chance. Internal comparison

approach would have taken some of these variations into account.

Effect Modification:

Analysis of lung cancer mortality among uranium miners has shown that

the level of radon induced risk is dependent not only on the magnitude of the

radiation dose but that the association can be modified by duration of

employment [5, 25, 47], years since last employment [5, 25, 47], and in some

instances, age at first employment [5]. Since the same carcinogenic agents

(alpha particles emitted from radon decay products) are being assessed for GI

cancer as for lung cancer, modifying effects by these three factors were also

assessed in this study.

In this study, effect modification was determined through stratification.

Separate risk estimates were derived for each strata of the presumed modifier.

Results from this study are suggestive that effect modification did occur for

duration of employment and years since last exposure. For example, the risk for

diagnosis of colorectal cancer were much higher among those with a

cumulative dose of 20-40 WLM distributed 3 or more years of employment

(RR=1.92, 95% CI 1.058-3.52) than those who experienced the same dose over a

shorter duration (RR=0.89, 95%CI 0.47-1.70). This inverse dose rate was also

observed in the literature for lung cancer mortality [5, 25, 47].

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Presentation of stratum-specific risk estimates provides an intuitive

assessment of effect modification; however, there are limitations to the

stratification approach. Using this approach is hampered by the relatively small

numbers of cancer cases observed for certain GI cancer sites. The lack of

statistical power prevents some modifying effects from being discerned.

Secondly, stratified approach does not provide a test of statistical significance

of the different risk estimates across strata. To address this issue, an interaction

term was created for duration of employment and cumulative radon dose in a

Poisson regression model. The results (Appendix VIII) confirm the stratified

regression approach showing a significant negative inverse relationship

between dose and duration of exposure for colorectal cancer.

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VIII) Poisson Regression: Grouped vs. Ungrouped Data

Poisson regression is routinely used for analysis of epidemiological data

from studies of large occupational cohorts [44]. It is traditionally implemented as

a grouped method of data analysis in which all exposure and covariate

information is categorized and person-time and events are tabulated for the

entire follow-up period. Grouped data can facilitate examination of trends

according to ordered categories of age, calendar time, and exposure level,

and increases the probability of models converging. From a practical

perspective, ungrouped data can be extremely intensive computationally for

large cohorts such as the Ontario Uranium Miners, even with today’s

computational capabilities. One major drawback of group data as noted by

Loomis and colleagues [48] is that for the purpose of estimating quantitative

exposure-response relations, information is lost in the categorization of exposure

data. Given that most studies to date used grouped data with established cut-

points, the current study also used the grouped data approach to facilitate

comparison.

As a sensitivity analysis, ungrouped data was also conducted for

colorectal and lung cancer. Results for ungrouped data shown in Appendix VIII

confirm grouped data used in the current study. Beta coefficient shows a

significant increase in cancer risks for colorectal and lung cancer with increase

in cumulative dose.

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Conclusions

The current study expanded the original study to include workers who

began employment since the last update in 1981 and extended the period of

follow-up to the end of 2004. Analysis of the data showed statistically significant

increases in diagnosis (incidence) and mortality of stomach and colorectal

cancers.

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178

Chapter 4 Tables and Figures

Table 30: Characteristics of the Ontario Uranium Miners study cohort.

Characteristics of cohort Characteristics

Cohort size 28,273

Follow-up period 1954-2004

Person-years of follow-up (incidence) 961,210

Person-years of follow-up (mortality) 974,687


<1900

1900 - 1919

1920 - 1939

1940 - 1959

1960+

Median

Range

28 (0.1)

2,310 (8.2)

13,006 (46.0)

11,288 (39.9)

1,641 (5.8)

1938

1887-1974

Age (years) at First Employment (n (%))

<22

22 - < 27

27 - < 34

34+

Median

Mean (SD)

6,073 (22)

7,691 (27)

7,262 (26)

7,247 (26)

27

28.9 (8.7)

179

Table 31: Incidence and mortality due to gastrointestinal cancer by age and

calendar period for a cohort (n=28,273) of Ontario uranium miners.

Esophageal* (ICD9-150)

Stomach* (ICD9-151)

Colorectal* (ICD9-153, 154, 159.0)

Characteristics Incidence

(n) Mortality (n)

Incidence (n)

Mortality (n)

Incidence (n)

Mortality (n)

Age at diagnosis/death

< 30 30 - < 40 40 - < 50 50 - < 60 60 - < 70 70- < 80 80+

Mean (SD) Year of diagnosis/death

1955-1959 1960-1969 1970-1979 1980-1989 1990-1999 2000-2004

Total

0 0 1 9 17 5 2

64.1 (8.6) ** 0 2 6 13 13 34

0 0 1 7 19 9 4

66.2 (8.6) 0 0 2 9 16 13 40

1 11 15 41 15 3

62.5 (9.9) ** 5 15 27 27 12 86

0 1 7 9 32 18 2

64.0 (9.6) 1 4 14 19 18 13 69

1 7 21 110 135 74 11

61.9 (9.6) ** 11 33 84 146 85 359

1 1 14 26 68 55 11

65.4 (10.6) 0 6 15 39 65 51 176

Note: * - First primary; **- Data from the Ontario Cancer Registry not available; SD- Standard

Deviation; ICD9-International Classification of Diseases, 9th Revision.

180

Table 32: Employment characteristics of the Ontario Uranium Miners study cohort

(as of December 31st, 2004)

Employment Characteristics Measures

Year at First Employment (n (%)) < 1958 1958-1967 1968-1978 1978+

5,953 (21.0) 8,451 (29.9) 6,039 (21.3) 7,829 (27.7)

Duration of Employment (n (%)) <2.0 yrs 2.0 - 3.0 yrs > 3.0 -< 7.0 yrs 7+ yrs Median Mean (SD)

Range

5,908 (20.9) 10,299 (36.4) 4,978 (17.61) 7,088 (25.1)

3.00 5.19 (5.8) 0.5 -22.5

Cumulative Radon (WLM) Exposure (n (%)) 0 >0 - 20 > 20 – 40 < 40 Mean (SD) Range

2,446 (8.7)

19,591 (69.3) 2,829 (10.0) 3,407 (12.0) 18.2 (38.1)

0-1169

181

Table 33: Average cumulative exposure to radon decay products (WLM) of Ontario Uranium Miners by age and

year at first employment, 1954-2004

n Mean Cum WLM

n Mean Cum WLM

n Mean Cum WLM

n Mean Cum WLM

< 22 868 36.50 1444 19.47 1723 5.97 2038 4.13

22 - < 27 1449 39.51 2491 25.12 1700 5.58 2051 3.97

27 -< 34 1750 43.28 2305 24.77 1396 5.44 1811 3.51

34+ 1886 47.14 2211 24.35 1220 4.00 1930 2.60

Total 5953 8451 6039 7830

Year of First EmploymentAge at First Employment

(years)<1958 1958-1967 1968-1977 1978+

182

Table 34: Average cumulative exposure to radon decay products (WLM) of Ontario Uranium Miners by age at

first employment by duration of employment, 1954-2004

n Mean Cum WLM

n Mean Cum WLM

n Mean Cum WLM

n Mean Cum WLM

< 22 1413 1.81 2082 6.61 940 19.03 1638 27.05

22 - < 27 1597 2.19 2904 8.58 1265 27.72 1925 38.43

27 -< 34 1413 2.34 2709 9.59 1351 29.21 1789 43.62

34+ 1485 2.43 2604 9.88 1422 29.90 1736 46.53

Total 5908 10299 4978 7088

Age at First Employment

(years)

Duration of Employment

< 2 years 2 - 3 years > 3 - < 7 years 7+ years

183

Table 35: Average cumulative exposure to radon decay products (WLM) of Ontario Uranium Miners by year at

first employment by duration of employment, 1954-2004

n Mean Cum WLM

n Mean Cum WLM

n Mean Cum WLM

n Mean Cum WLM

<1958 809 6.62 2268 19.95 1662 43.66 1214 107.42

1958-1967 1978 3.16 3888 10.15 1284 43.08 1301 77.32

1968-1977 1144 0.73 1919 1.58 955 3.90 2021 12.20

1978+ 1977 0.26 2224 1.19 1077 3.09 2552 8.40

Total 5908 10299 4978 7088

Year at First Employment

Duration of Employment

< 2 years 2 - 3 years > 3 - < 7 years 7+ years

184

Table 36: Age and period adjusted relative risks of diagnoses (1964-2004) and deaths (1954-2004) of

esophageal, stomach, colorectal, gastrointestinal, and lung cancer associated with cumulative exposure to

radon decay products (Working Level Months, 10-year lag) for Ontario Uranium Miners.

Cases PY RR (95% CI)* Deaths PY RR (95% CI)*

0 2 335,778 - 4 337,470 -> 0 - 20 18 454,983 2.59 (0.57-11.8) 20 461,812 1.44 (0.47-4.43)> 20 - 40 9 77,334 6.37 (1.30-31.2) 9 79,272 2.71 (0.79-9.30)

> 40 5 93,115 2.72 (0.50-14.9) 7 96,133 1.51 (0.42-5.48)Total 34 961,210 P trend = 0.59 40 974,687 P trend = 0.74

0 11 335,778 - 7 337,470 -> 0 - 20 43 454,983 1.94 (0.94-3.96) 37 461,812 2.65 (1.11-6.32)> 20 - 40 14 77,334 2.51 (1.08-5.80) 10 79,272 2.74 (0.99-7.63)


0 57 335,778 - 24 337,470 -> 0 - 20 186 454,983 1.15 (0.84-1.58) 89 461,812 1.19 (0.73-1.93)> 20 - 40 47 77,334 1.42 (0.94-2.12) 21 79,272 1.20 (0.65-2.22)


0 70 335,778 - 35 337,470 -> 0 - 20 247 454,983 1.33 (0.99-1.77) 146 461,812 1.49 (1.00-2.23)> 20 - 40 70 77,334 1.76 (1.24-2.49) 40 79,272 1.69 (1.05-2.73)


0 78 335,778 - 73 337,470 -> 0 - 20 386 454,983 2.25 (1.74-2.90) 331 461,812 1.89 (1.44-2.47)> 20 - 40 120 77,334 3.18 (2.36-4.29) 98 79,272 2.47 (1.74-3.39)

> 40 263 93,115 5.16 (3.94-6.75) 230 96,133 4.22 (3.19-5.61)Total 847 961,210 P trend < 0.01 732 974,687 P trend < 0.01

Notes:* - Adjusted for attained age and period; WLM – Working Level Month, RR - Relative Risk; CI-Confidence Interval; and, ICD-9-International Classification of Diseases, 9th Revision; GI - Gastrointestinal Cancer (ICD-9: 150, 151, 153, 154, 159.0); and PY- Person Years.

Incidence (1964-2004) Mortality (1954-2004)

Sto

mac

h

(151

)

Cancer Site

(ICD-9)

Cumulative Radon Dose (WLM)

Colo

rect

al

(153

, 154

,

159.

0)

Eso

phag

us

(1

50)

Gas

tro-

inte

stin

al

Lung

(162

)

185

Table 37: Age and period adjusted relative risks of diagnoses (1964-2004) of esophageal, stomach, colorectal,

gastrointestinal, and lung cancer associated with cumulative exposure to radon decay products (Working

Level Months, 10-year lag) stratified by duration of employment for Ontario Uranium Miners, 1954-2004

Cases P Y RR (95% CI)* C ases PY RR (95% CI) *

0 1 203.994 - 1 131.784 -> 0 - 20 16 320.416 4.01 (0 .50-32.2) 2 134.565 1 .07 (0 .8-13.2)

> 20 - 40 4 29.402 10.5 (1 .01-100) 5 47.932 3 .91 (0 .38-39.7)> 40 1 11.203 6.75 (0 .40-114) 4 81.912 1 .55 (0 .14-16.6)T o tal 22 565.015 P tren d = 0 .11 12 396.193 P t ren d = 0.91

0 9 203.994 - 2 131.784 -> 0 - 20 32 320.416 1.48 (0 .66-3 .33) 11 134.565 4 .78 (0 .92-21.7)

> 20 - 40 8 29.402 3.00 (1 .09-8 .24) 6 47.932 3 .16 (0 .54-17.0)> 40 1 11.203 0.83 (0 .10-6 .74) 17 81.912 4 .41 (0 .91-21.1)T o tal 50 565.015 P tren d = 0 .51 36 396.193 P t ren d = 0.32

0 38 203.994 - 19 131.784 -> 0 - 20 123 320.416 0.91 (0 .62-1 .35) 63 134.565 1 .88 (1 .08-3 .27)

> 20 - 40 13 29.402 0.89 (0 .47-1 .70) 34 47.932 1 .92 (1 .05-3 .52)> 40 4 11.203 0.67 (0 .23-1 .91) 65 81.912 1 .89 (1 .08-3 .32)T o tal 178 565.015 P tren d = 0 .49 181 396.193 P t ren d = 0.37

0 48 203.994 - 22 131.784 -> 0 - 20 171 320.416 1.10 (0 .78-1 .55) 76 134.565 2 .10 (1 .27-3 .49)

> 20 - 40 25 29.402 1.45 (0 .87-2 .39) 45 47.932 2 .17 (1 .26-3 .77)> 40 6 11.203 0.84 (0 .36-2 .00) 86 81.912 2 .12 (1 .26-3 .54)T o tal 250 565.015 P tren d = 0 .82 229 396.193 P t ren d = 0.25

0 51 203.994 - 27 131.784 -> 0 - 20 291 320.416 1.91 (1 .39-2 .62) 95 134.565 2 .80 (1 .79-4 .37)

> 20 - 40 33 29.402 1.90 (1 .21-2 .99) 87 47.932 4 .61 (2 .93-7 .23)> 40 11 11.203 1.50 (0 .77-2 .90) 252 81.912 6 .89 (4 .52-10.5)T o tal 386 565.015 P tren d = 0 .62 461 396.193 P t ren d < 0.01

N otes:* - A djusted for a tta ined age and per iod; W LM – W orking Leve l M onth , RR - Re la tive R isk ; CI-C onfidence In te rva l; and, ICD -9-In te rnational C las sifica tion o f D iseases, 9th Revision; G I - G astroin testina l C ancer ( IC D-9: 150, 151, 153 , 154, 159.0); and PY- P erson Years;

Sto

mac

h

(151

)

Gas

tro

-

inte

stin

al> 3 years o f em plo ym ent

Lu

ng

(162

)

Eso

pha

gu

s

(150

)C ancer

Site ( ICD-9)

Cum ulative Radon D ose

(WLM)

< = 3 years of emp lo ym en t C

olo

rect

al

(153

, 154

,

159

.0)

186

Table 38: Age and period adjusted relative risks of deaths (1954-2004) due to esophageal, stomach, colorectal,


Level Months, 10-year lag) stratified by duration of employment for Ontario Uranium Miners, 1954-2004

Deaths PY RR (95% CI)* Deaths PY RR (95% CI)*

0 2 205,049 - 2 132,421 -> 0 - 20 15 324,903 2.22 (0.48-10.3) 5 136,909 0.77 (0.14-4.39)> 20 - 40 5 30,034 6.50 (1.19-35.7) 4 49,238 0.70 (0.11-4.29)


0 7 205,049 - 0 132,421 -> 0 - 20 29 324,903 1.76 (0.71-4.33) 8 136,909 Non-est> 20 - 40 6 30,034 2.87 (0.90-9.07) 4 49,238 Non-est

> 40 1 11,391 1.00 (0.11-8.47) 14 84,742 Non-estTotal 43 571,377 P trend = 0.69 26 403,310 P trend = NA

0 19 205,049 - 5 132,421 -> 0 - 20 64 324,903 0.89 (0.51-1.54) 25 136,909 2.77 (1.00-7.66)> 20 - 40 3 30,034 0.36 (0.10-1.23) 18 49,238 2.79 (0.97-8.04)


0 28 205,049 - 7 132,421 -> 0 - 20 108 324,903 1.21 (0.77-1.90) 38 136,909 3.01 (1.28-7.07)> 20 - 40 14 30,034 1.31 (0.67-2.56) 26 49,238 2.74 (1.12-6.69)


0 48 205,049 - 25 132,421 -> 0 - 20 258 324,903 1.62 (1.17-2.25) 73 136,909 2.21 (1.37-3.57)> 20 - 40 27 30,034 1.47 (0.90-2.38) 71 49,238 3.61 (2.23-5.85)

> 40 10 11,391 1.30 (0.65-2.59) 220 84,742 5.75 (3.67-8.98)Total 343 571,377 P trend = 0.99 389 403,310 P trend < 0.01

Cancer Site (ICD-9)

Cumulative Radon Dose

(WLM)

< = 3 years of employment > 3 years of employment

Notes:* - Adjusted for attained age and period; 'Non-est.' - risk estimate could not be estimated; WLM – Working Level Month, RR - Relative Risk; CI-Confidence Interval; and, ICD-9-International Classification of Diseases, 9th Revision; GI - Gastrointestinal Cancer (ICD-9: 150, 151, 153, 154, 159.0); and PY- Person Years

Colo

rect

al

(153

, 154

,

159.

0)

Eso

phag

us

(1

50)

Sto

mac

h

(151

)

Gas

tro-

inte

stin

al

Lung

(162

)

187



Level Months, 10-year lag) stratified by years since last employment for Ontario Uranium Miners, 1954-2004

Cases PY RR (95% CI)* C ases PY RR (95% CI)*

0 2 168.502 - 0 167.276 -> 0 - 20 5 185.702 1,64 (0,28-10,0) 13 269.281 Non-est

> 20 - 40 3 13.512 6,47 (0,96-43,2) 6 63.822 Non-est> 40 3 21.220 2,34 (0,34-16,2) 2 71.895 Non-estTotal 13 388.936 P tren d = 0.55 21 572.274 P tren d = NA

0 11 168.502 - 0 167.276 -> 0 - 20 28 185.702 3,30 (1,54-7,07) 15 269.281 Non-est

> 20 - 40 8 13.512 4,85 (1,88-12,6) 6 63.822 Non-est> 40 12 21.220 2,91 (1,20-7,05) 6 71.895 Non-estTotal 59 388.936 P tren d = 0.36 27 572.274 P tren d = NA

0 40 168.502 - 17 167.276 -> 0 - 20 112 185.702 2,49 (1,67-3,71) 74 269.281 0,60 (0,35-1,01)

> 20 - 40 26 13.512 5,29 (3,17-8,83) 21 63.822 0,65 (0,34-1,23)> 40 42 21.220 3,36 (2,10-5,37) 27 71.895 0,68 (0,37-1,25)Total 220 388.936 P tren d < 0.01 139 572.274 P t ren d = 0.90

0 53 168.502 - 17 167.276 -> 0 - 20 145 185.702 2,66 (1,87-3,76) 102 269.281 0,82 (0,49-1,36)


0 57 168.502 - 21 167.276 -> 0 - 20 203 185.702 4,39 (3,21-6,00) 183 269.281 1,20 (0,76-1,88)


N otes:* - A djusted for a tta ined age and period; 'Non-est.' - r isk estim ate could not be estim ated; W LM – W orking Level M onth, RR - R elative Risk; CI-Confidence In terva l; and, ICD-9-International C las sification of Diseases, 9th Revision; GI - Gastrointestinal Cancer (ICD-9: 150, 151, 153, 154, 159.0); and P Y- P erson Years;

> 26 Years

Eso

pha

gu

s

(150

)

Sto

mac

h

(151

)

Col

ore

ct

al (

153

,

154

, 15

9.0)

Gas

tro

-

inte

stin

al

Lu

ng

(162

)

C ancer Site

( ICD-9)

Cumulative Radon D ose

(WLM)

< = 26 Y ears

188

Table 40: Age and period adjusted relative risks for deaths (1954-2004) due to esophageal, stomach,

colorectal, gastrointestinal, and lung cancer associated with cumulative exposure to radon decay products

(Working Level Months, 10-year lag) stratified by years since last employment for Ontario Uranium Miners, 1954-

2004


0 4 166,244 - 0 171,226 -> 0 - 20 9 186,124 1.61 (0.44-5.90) 11 275,688 Non-est> 20 - 40 2 12,877 2.08 (0.35-12.2) 7 66,395 Non-est


0 6 166,244 - 0 171,226 -> 0 - 20 25 186,124 6.02 (2.30-15.7) 13 275,688 Non-est> 20 - 40 5 12,877 5.79 (1.70-19.7) 5 66,395 Non-est


0 15 166,244 - 9 171,226 -> 0 - 20 44 186,124 2.71 (1.42-5.13) 45 275,688 0.69 (0.33-1.40)> 20 - 40 12 12,877 5.66 (2.57-12.5) 9 66,395 0.49 (0.20-1.24)


0 25 166,244 - 10 171,226 -> 0 - 20 78 186,124 3.22 (1.97-5.27) 68 275,688 0.93 (0.48-1.81)> 20 - 40 19 12,877 5.07 (2.72-9.43) 21 66,395 1.03 (0.48-2.19)


0 49 166,244 - 24 171,226 -> 0 - 20 162 186,124 3.69 (2.62-5.19) 169 275,688 0.96 (0.63-1.48)> 20 - 40 55 12,877 9.80 (6.59-14.6) 43 66,395 0.90 (0.54-1.49)

> 40 164 20,967 11.33 (8.03-15.9) 66 75,166 1.12 (0.70-1.79)Total 430 386,212 P trend < 0.01 302 588,475 P trend = 0.32

Cancer Site (ICD-9)


(WLM)

< = 26 Years > 26 Years

Notes:* - Adjusted for attained age and period; 'Non-est.' - risk estimate could not be estimated; WLM – Working Level Month, RR - Relative Risk; CI-Confidence Interval; and, ICD-9-International Classification of Diseases, 9th Revision; GI - Gastrointestinal Cancer (ICD-9: 150, 151, 153, 154, 159.0); and PY- Person Years

Eso

phag

us

(150

)

Sto

mac

h

(151

)

Colo

rect

al (1

53,

154,

159

.0)

Gas

tro-

inte

stin

al

Lung

(162

)

189



Level Months, 10-year lag) stratified by age at first employment for Ontario Uranium Miners, 1954-2004

Cases PY RR (95% CI)* Cases PY RR (95% CI)*

0 0 176,735 - 2 159,043 -> 0 - 20 12 257,867 Non-est 6 197,116 0,90 (0,16-4,94)> 20 - 40 6 39,450 Non-est 3 37,884 1,87 (0,28-12,4)

> 40 1 44,082 Non-est 4 49,033 1,77 (0,29-10,8)Total 19 518,134 P trend = NA 15 443,076 P trend = 0.31

0 1 176,735 - 10 159,043 -> 0 - 20 9 257,867 3,36 (0,35-31,8) 34 197,116 1,82 (0,85-3,90)> 20 - 40 1 39,450 1,53 (0,08-28,2) 13 37,884 2,80 (1,17-6,74)

> 40 2 44,082 2,33 (0,17-31.0) 16 49,033 2,43 (1,03-5,70)Total 13 518,134 P trend = 0.80 73 443,076 P trend = 0.14

0 8 176,735 - 49 159,043 -> 0 - 20 54 257,867 1,77 (0,82-3,82) 132 197,116 1,07 (0,75-1,52)> 20 - 40 15 39,450 2,70 (1,11-6,57) 32 37,884 1,28 (0,80-2,04)

> 40 18 44,082 2,58 (1,08-6,14) 51 49,033 1,43 (0,97-2,27)Total 95 518,134 P trend = 0.08 264 443,076 P trend = 0.04

0 9 176,735 - 61 159,043 -> 0 - 20 75 257,867 2,18 (1,06-4,48) 172 197,116 1,19 (0,87-1,63)> 20 - 40 22 39,450 3,39 (1,51-7,58) 48 37,884 1,55 (1,03-2,31)


0 11 176,735 - 67 159,043 -> 0 - 20 102 257,867 2,83 (1,49-5,38) 284 197,116 2,07 (1,55-2,74)> 20 - 40 37 39,450 6,14 (3,07-12,2) 83 37,884 2,64 (1,88-3,70)

> 40 75 44,082 10,1 (5,27-19,5) 188 49,033 4,27 (3,16-5,76)Total 225 518,134 P trend < 0.01 622 443,076 P trend < 0.01

Cancer Site (ICD-9)


(WLM)


Lung

(162

)

Notes:* - Adjusted for attained age and period; 'Non-est.' - risk estimate could not be estimated; WLM – Working Level Month, RR - Relative Risk; CI-Confidence Interval; and, ICD-9-International Classification of Diseases, 9th Revision; GI - Gastrointestinal Cancer (ICD-9: 150, 151, 153, 154, 159.0); and PY- Person Years; *

Colo

rect

al

(153

, 154

,

159.

0)

Eso

phag

us

(150

)

Sto

mac

h

(151

)

Gas

tro-

inte

stin

al

190

Table 42: Age and period adjusted relative risks of deaths (1964-2004) due to esophageal, stomach,

colorectal, gastrointestinal, and lung cancer associated with cumulative exposure to radon decay

products (Working Level Months, 10-year lag) stratified by age at first employment for Ontario Uranium

Miners, 1954-2004


0 0 177,081 - 4 160,389 -> 0 - 20 9 260,144 Non-est. 11 201,668 0,71 (0,21-2,33)> 20 - 40 6 40,184 Non-est. 3 39,088 0,73 (0,16-3,40)

> 40 1 45,034 Non-est. 6 51,099 0,98 (0,26-3,69)Total 16 522,443 P trend = NA 24 452,244 P trend = 0.62

0 1 177,081 - 6 160,389 -> 0 - 20 4 260,144 1,26 (0.10-15,3) 33 201,668 3,00 (1,18-7,61)> 20 - 40 1 40,184 1.27 (0.06-26,3) 9 39,088 3,17 (1,07-9,40)

> 40 3 45,034 2.91 (0.22-39.3) 12 51,099 2,94 (1,03-8,37)Total 9 522,443 P trend = 0.24 60 452,244 P trend = 0.50

0 5 177,081 - 19 160,389 -> 0 - 20 23 260,144 1,27 (0,45-3,59) 66 201,668 1,20 (0,69-2,09)> 20 - 40 6 40,184 1,51 (0,43-5,29) 15 39,088 1,17 (0,57-2,38)


0 6 177,081 - 29 160,389 -> 0 - 20 36 260,144 1,63 (0,64-4,10) 110 201,668 1,46 (0,93-2,27)> 20 - 40 13 40,184 2,70 (0,97-7,53) 27 39,088 1,46 (0,84-2,54)


0 10 177,081 - 63 160,389 -> 0 - 20 84 260,144 2,21 (1,13-4,35) 247 201,668 1,78 (1,32-2,39)> 20 - 40 30 40,184 4,29 (2,04-8,97) 68 39,088 2,12 (1,48-3,05)

> 40 54 45,034 6,10 (3,02-12,3) 176 51,099 3,92 (2,86-5,35)Total 178 522,443 P trend < 0.01 554 452,244 P trend < 0,01

Notes:* - Adjusted for attained age and period; 'Non-est.' - risk estimate could not be estimated; WLM – Working Level Month, RR - Relative Risk; CI-Confidence Interval; and, ICD-9-International Classification of Diseases, 9th Revision; GI - Gastrointestinal Cancer (ICD-9: 150, 151, 153, 154, 159.0); and PY- Person Years; *

Colo

rect

al

(153

, 154

,

159.

0)Cancer Site

(ICD-9)


(WLM)


Eso

phag

us

(150

)

Sto

mac

h

(151

)

Gas

tro-

inte

stin

al

Lung

(162

)

191

Chapter 5: Summary Discussion and Conclusions

Chapter 5: Summary Discussion and Conclusions24

192

Summary Discussions Adverse health effects associated with exposure to radiation has been a

topic of intense research since soon after the discovery of radioactivity in the

late 1800s. It was clear from the beginning that exposure to radiation at high

doses had immediate and severe consequences including burns, vomiting and

even death. Later came the discovery that decaying radioactive material, such

as uranium-238, produces ionizing radiation capable of detaching (ionizing) the

electrons from the atoms and molecules of living tissue causing cellular damage

and alterations in genetic material producing the potential for development of

cancer.

Despite the known adverse health effects, radiation-based technology

has tremendously enhanced our quality of life through medicine, research,

construction, and energy production, the benefits of which cannot be ignored.

As such, the majority of research conducted in this area has been and

continues to be focusing on providing evidence-based knowledge to assist

regulatory bodies in establishing safe limits for radiation exposure. The existence

of multiple collaborative and international agencies such as Committees

examining the Biological Effects of Ionizing Radiation (BEIR), United Nations

Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), and

International Commission on Radiological Protection (ICRP) attests to the

importance of this subject area.

193

Cohorts of uranium miners world-wide have been invaluable in building

this knowledge base. In fact, it has become the primary data source for setting

guidelines on limits for exposure to alpha particles emitted from radon and its

decay products. Specifically, these guidelines are based almost exclusively on

the body of evidence supporting a ‘causal’ link between inhaled radon and

excess lung cancer mortality.

While the evidence of the effects of radon on lung cancer mortality is not

in question, the cancer effects on other organs, particularly major organs along

the gastrointestinal tract, remain inconclusive. The current study has been

designed to address this very knowledge gap. Specifically, this study focuses on

the potential risks associated with exposure to ingested alpha particles emitted

from radon and its decay products to the major organs located along the GI

tract. Given that Ontario uranium miners were exposed to lower doses than

other cohorts, results from this study will also contribute to the body of

knowledge about non-lung cancer effects at low doses.

In this study, significant increases were observed for cancers of the

stomach and colon-rectum for those miners with cumulative exposure of more

than 40 WLM, compared to those with 0 WLM, for both incidence and mortality.

Adjusted relative risks with a 10-year lag were 2.30 (95%CI 1.02-5.17) and 1.56

(95%CI, 1.07-2.27) for incidence of cancer of the stomach, and colorectal

cancer respectively. For mortality, significant increases were also observed for

194

stomach (RR=2.90, 95%CI 1.11-7.63) and colorectal cancers (RR=1.74, 95%CI

1.01-2.99).

Causal Inferences

While this study shows increased risk associated with exposure to ionizing

radiation for stomach and colorectal cancers, no one epidemiological

investigation can equivocally demonstrate a causal effect. Any discussion of

causality in chronic disease epidemiology will invariably evoke a discussion on

the meaning of ‘cause’ and whether the evidence supports the Bradford Hill

criteria often used in assessing causation for statistical associations found in

observational studies [1]. While the focus of this thesis is not to embark on

philosophical discussions of causality, comparisons with other studies with

respect to the biological plausibility, strength, and consistency of the

associations found in this study will aid in the interpretation of the current study’s

results in light of previous findings.

Biological Plausibility

Energy from alpha particles, such as that emitted from radon decay

products, is capable of removing electrons from molecules of living tissues [2].

This ionization has been shown to cause damage to host genetic material [2].

Although living organisms have the ability to repair damage, persistent and

repeated exposure can lead to errors in the repair mechanism that may

eventually lead to malignant diseases [2]. Genetic epidemiology has provided

195

some support for this postulate. Smerhovsky and colleagues examined

aberrations of chromosomes of 225 subjects and found that chromatid breaks

were significantly associated with radon exposure [3]. Furthermore, Meszaros

and colleagues observed that these aberrations persisted well after miners had

stopped working (i.e., after exposure has ended) [4].

An experimental study on human subjects ha also been conducted in the

past to determine “the fate of radon ingested by man” [5]. In this study, human

subjects drank known quantities of dissolved radon and its decay products and

doses to the stomach and other GI organs were estimated [5, 6]. The stomach

was shown to incur the highest body burden of ingested radon and its decay

products.

The significant increases in GI cancer risks associated with exposure to

radon decay products observed in this study are biologically consistent with the

hypothesis that direct contact with ingested radon can lead to long-term health

effects. Given that the digestion process takes approximately 41 hours to

complete (from ingestion to excretion) [7, 8], ingested radon decay products

with a short half-life of 51 minutes would have sufficient time to decay (from

radon (222Rn) to polonium (214Po)) and release their destructive energy to

organs/tissues along the GI tract [5, 9]. Although most of the dose will be to the

stomach, residual smaller doses will be delivered to the colon and rectum over a

long transit time. The inverse dose rate indicates smaller doses delivered over

longer periods can also have significant impacts.

196

Strength of Associations

The standard practice of most research is to assess the significance of

study results by comparing them to statistical or clinical criteria. From a statistical

perspective, a 95% confidence limit (or a p-value) is the arbitrary interval

commonly used as a benchmark for establishing whether or not the observed

results occurred by chance. If the lower confidence interval is above 1, the risk is

said to be ‘significantly’ increased. Conversely, if the upper confidence limit is

below 1, then the risk is said to be ‘significantly’ decreased. Once statistical

significance has been established, the size of the point estimate can be used to

assess the strength of the association. For example, one might conclude that a

hypothetical risk estimate of 4.0 (95% CI; 3.5-4.5) represents a stronger

association (4-fold increase) as compared to a risk estimate of 2.0 (95% CI; 1.5-

2.5) or no significant association (RR= 1.0, 95% CI; 0.5-1.5).

With the exception of risk estimates for esophageal cancer, results from

this study appear to satisfy this criterion in that the lower limit of the confidence

intervals for most of the risk estimates were above unity. For example, an almost

3-fold increase of risk of stomach cancer (RR=2.90, 95%CI; 1.11-7.63) was

observed for miners who had a cumulative dose of greater than 40 WLM as

compared to miners with a cumulative dose of 0 WLM, while for colorectal

cancer there was a 74 % increase in risk (RR=1.74, 95% CI; 1.01-2.99).

197

Consistency of Associations

Of the three primary cancers of interest in the current study, results for

stomach cancer mortality were most consistent with the results found in the

literature. The level of agreement appears to be modified by the size of the

study in which the risk estimates were derived. Larger studies such as the Ontario

uranium miners, the German uranium company and the pooled 11 cohorts by

Darby and colleagues showed statistically significant increases in stomach

cancer mortality associated with exposure to ionizing radiation [10, 11]. Smaller

studies such as those by the French [12], Czech [13] and in Newfoundland [14]

showed an increased risk, but not a statistically significant one.

For deaths due to esophageal cancer, consistency was difficult to assess

given that most studies (including the current study) were based on very few

observed cases. Results from the studies to date show a large degree of

variation in the risk estimates which may be due to small numbers. For colorectal

cancer mortality, consistency was also difficult to assess given that different

coding was used for this disease grouping in different studies. Tomasek [13]

coded colon (ICD-9: 152 & 153) separate from rectum (154). Darby and

colleagues [15] only looked at the rectum. Furthermore, studies conducted to

date have not examined the risk of diagnosis (incidence). Therefore, results from

incidence analyses for all three cancer types could not be compared to other

studies.

198

Healthy Worker Effect

The healthy worker effect (HWE) refers to a type of selection bias whereby

healthy workers are preferentially selected for employment. Because individuals

who are employed are generally healthier than those who are not employed,

any comparison of the health status of the workers to the general population

would likely result in an artifact of reduced risk.

The HWE is unlikely to be a major factor in this study since internal

comparisons were used as the main method of analysis rather than using

external standards. Furthermore, cancer studies were less likely to be affected

by the HWE since cancer tends to occur in older populations. Given that the

average age at first employment of miners was 29 years, these miners would not

have been subjected to selection bias based on cancer status (or cancer

potential) on the part of the employer.

Study Limitations

Potential Effects of Smoking and Diet on Risk Estimates

In this study, analysis of the Ontario Uranium Miners showed a significant

increase in cancer risk for stomach and colorectal cancers with increased

cumulative doses of radon decay products. However, the strength of this

association must be interpreted in light of its potential limitations, particularly, its

limited inability to control for other important confounding factors such as

smoking and diet.

199

By definition, a confounder must be associated with the cumulative dose

of radon decay products (exposure) and cancer diagnosis or mortality

(outcome of interest) and cannot be in the causal pathway. Smoking satisfies

this definition. Therefore, ideally, the true effect between cumulative dose of

radon decay products and GI cancer risks should take smoking into account.

Unfortunately, it was not possible to examine the effects of smoking in the

current study since the individual level data on smoking was not collected for all

uranium miners. As such, the true effect of smoking on the risk estimate could

not be assessed in this study. That said, to be a confounder, it must be

associated with both the disease and the exposure of interest. Smoking has

been associated with different cancer sites. However, there is no evidence to

believe that smoking is related to the level of radon decay products.

Despite this limitation, the potential role of smoke on GI cancer risk,

particularly for stomach cancer has been previously examined by the Industrial

Disease Standards Panel [16] that concluded that “Since cigarette smoking is at

most a weak risk factor for cancer of the stomach, any differences between the

miners and the comparison population in terms of smoking habits are probably

unimportant here.” [16], a view that is also shared by others [17, 18].

Furthermore, it has been noted that smoking was a common behaviour for the

majority of the miners [19, 20] . As such, regardless of individual smoking status,

one could argue that all miners were exposed to tobacco smoke either directly

200

or indirectly through second-hand smoke. Given these views, the lack of

smoking information will not likely have a significant impact on the risk estimate.

As in the case with smoking, no data on diet was collected from miners.

Although diet is an important factor in the development of GI cancer [21], the

relationship of diet to the primary exposure (WLM) is not clear. It is more likely

that diet is located along the causal pathway, which makes it more likely to be

an effect modifier of stomach cancer than a confounder. However, without

individual level data on diet, adjustment (or stratified analysis) for diet could not

be carried out and as such, its effects on the risks estimated cannot be known

with certainty. A sensitivity analysis was attempted using place of birth as a

crude proxy measure of diet, however, due to a large number of missing place

of birth data, number of miners with valid information for place of birth was

small, resulting in non-convergence of models due to empty cells.

Loss to Follow-up

One of the most important limitations of this study is the misclassification of

disease status due to loss to follow-up. Chapter 3 explored the potential impact

of the loss on the risk estimates. It was found that the losses can result in an

overestimation of risk due to the fact that more cases were being lost from the

lower exposed group than the higher exposed group. The issue of loss to follow-

up (or misclassification of disease status) is not unique to this study. Analysis of

the Australian cohort conducted by Woodward and colleagues revealed that

health status of 36% of cohort members could not be determined due to

201

migrant workers returning to their native countries following the employment

[22].

In order to minimize the loss to follow-up, a number of options could have

been considered if resources were unlimited. For example, manual search of the

National Death Index (NDI) of the US might lead to a few matches for miners

who immigrated to the US and experienced the event. However, this proportion

is expected to be very small and linking to the NDI will still not resolve the issue

completely since many of the miners were born in Europe (e.g., England, Italy,

and Portugal) and there is a possibility that these miners returned to their native

countries after retirement. As such, vital statistics of miners who return to Europe

(or elsewhere) would remain untraceable.

Computerized Linkage

There is little doubt regarding the value of computerized record linkage in

epidemiologic research. However, there are also limitations to CRL and these

limitations have been well documented by Howe [23]. In particular, the

limitations of computerized record linkage most relevant to this study are as

follows.

No linkage is perfect. In Chapter 3, linkage results from the current study

(provincial) were compared to the previous linkage conducted at the national

level. Deaths in Ontario were identified in the current linkage but missed by the

Muller linkage. Similarly, there were deaths found in the Muller linkage that

occurred in Ontario that were also missed in the current linkage.

202

Linkage is both quantitative and qualitative. The quantitative aspects of

linkage are at the beginning of the linkage where initial passes of the linkage

process are driven by rules and weights of unique identifiers to determine the

probability of matches between records. However, invariably, there is a

proportion of records remaining that could not be resolved through quantitative

means. Resolution of the remaining “grey area” depends on the experience

and judgment of the researcher. In this study, any potential biases associated

with resolving grey area were removed by blinding the linkage researcher to the

exposure of the worker.

Unique identifiers are not always ‘unique’. Identifiers such as social security

numbers are intended to be a unique identifier of individuals within populations.

However, there are instances where the same number was either issued to two

or more different individuals, or they are recorded in error. Such duplications can

create linkage errors.

Conclusions and Future Research

In this study, the incidence and mortality experience of a cohort of 28, 273

uranium miners in relation to their cumulative exposure to radon decay products

was investigated. The results of this analysis showed that the incidence and

mortality for stomach and colorectal cancers were significantly higher when

comparing the highest exposed group to the lowest exposed group.

203

While there are strengths to this study, it is also important to note that there

are also significant limitations that could be resolved in future investigations. In

particular is the issue of potential misclassification of disease status due to loss to

follow-up. This issue could be resolved, in part, by linking the cohort to national

level data in order to determine disease status of those who moved outside of

Ontario. While this would significantly reduce the number of miners misclassified,

miners who chose to leave Canada to return to their native country will remain

a potential, albeit, small limitation to the study.

This study focuses on GI cancer as an outcome of interest. Although

beyond the scope of this study, ionizing radiation has also been implicated in

the development of cardiovascular disease. This cohort would be amendable

to evaluating cardiovascular risks associated with exposure to ionizing radiation.

Finally, this study focused on ionizing radiation from alpha particles. It has been

observed that uranium miners are also exposed to gamma radiation. The health

effects associated with gamma radiation represent another knowledge gap in

the literature. This was not evaluated in the current study due to the lack of data

for miners working before 1981. Future work should consider developing

statistical models to estimate historical gamma doses that could potentially be

incurred by miners and the potential risk associated with these exposures.

204


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of chromosomal aberrations. Mutat Res, 2002. 514(1-2): p. 165-76.

4. Meszaros, G., G. Bognar, and G.J. Koteles, Long-term persistence of chromosome aberrations in

uranium miners. J Occup Health, 2004. 46(4): p. 310-5.

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Workers, IDRC Publication 30, Oxford: Pergamon Press,. 1979.

8. International Commission on Radiological Protection (ICRP), Human Alimentary Tract Model for

Radiological Protection, IDRC Publication 100, . 2006, Oxford, UK: Elsevier Ltd.

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Radiol Prot, 2002. 22(4): p. 389-406.

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collaborative analysis of 11 studies. J Natl Cancer Inst, 1995. 87(5): p. 378-84.

11. Kreuzer, M., et al., Radon and risk of extrapulmonary cancers: results of the German uranium

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12. Laurier, D., et al., An update of cancer mortality among the French cohort of uranium miners:

extended follow-up and new source of data for causes of death. Eur J Epidemiol, 2004. 19(2): p.

139-46.

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West Bohemia. Lancet, 1993. 341(8850): p. 919-23.

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mortality follow-up of the Newfoundland fluorspar cohort. Health Phys, 2007. 92(2): p. 157-69.

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Swedish iron miners. Environ Health Perspect, 1995. 103 Suppl 2: p. 45-7.

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117-26.

18. Siemiatycki, J., et al., Degree of confounding bias related to smoking, ethnic group, and

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miners. Health Phys, 2000. 79(4): p. 365-72.

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112-21.

207

Appendices Appendix I: Record Layout of Work History File ................................................................. 208

Appendix II: National Dose Registry ......................................................................................... 211

Appendix III: SAS Syntax (Person Years, Grouping, and Model)................................. 212

Appendix IV: Sample Data for Miner John Doe ................................................................. 215

Appendix V: Sensitivity Analysis I – Lagging .......................................................................... 216

Appendix VI: Sensitivity Analysis II – Excluding Miners with a history of Gold

mining .................................................................................................................................................... 221

Appendix VII: Sensitivity Analysis IV – Pre-1968 (Miners who start employment

prior to 1968) ....................................................................................................................................... 221

Appendix VII: Sensitivity Analysis IV – Pre-1968 (Miners who start employment

prior to 1968) ....................................................................................................................................... 222

Appendix VIII: Ungrouped Poisson Regression Model and Statistical Test of

Interaction............................................................................................................................................ 223

208

Appendix I: Record Layout of Work History File The entire Mining Master File that contains information on approximately 83,979

miners who had ever worked as a miner (of all types of ores) in Ontario up to

1986. It contains demographic information (names, date of birth, place of birth,

and sex), and employment information (months worked, ores mined, mines and

mining areas, exposure to radon and its decay products). The MMF was

discontinued in 1986.

To examine health effects associated with exposure to ionizing radiation, a

database containing a subset of miners who had ever worked in Ontario

uranium mines was extracted for analysis. Since the focus of this extraction was

based on the work history of thee miners, this subset of data hereafter will be

refer to as the Work History File (WHF).

The Work History File (WHF) contains 312,677 records for 26,320 miners. The

original record layout and information of the original source data is maintained

in this submission for linkage in order to avoid loss of information.

Record Layout of the Work History File

The WHF consists of several types of records of variable length. Each record

contains the unique Mining Certificate Number (MCERT) and mining number

that could be concatenated to creation of a single observation for each

individual miner. For each miner, the following record was extracted in the WHF:

Record Sequence

Variable Name

Description

MCERT Unique miner certificate number

NMINER Consecutive miner's number on file

SNAME Miner's surname

FGIV Miner's first given name

SGIV Miner's second given name

ALTSUR Miner's alternate surname if it exists

ALTGIV Miner's alternate given name if it exits

DYR Year of death if miner died

First Row

X Number of employment records for miner



BYR Year of birth

BMTH Month of birth

BDAY Day of birth

Second Row

BPLACE Place of birth

209

Record Sequence

Variable Name

Description

USPYR Year of qualification in study

SPECIAL If = B, then miner worked in Eldorado, then total

radiation can not be determined

ASBESTOS If = Y, then miner worked in an asbestos mine,

otherwise it = No

EMILL If = Y, then miner worked in a uranium mill, then

total radiation can not be determined

U_NONT Uranium exposure outside of Ontario

URAN_EX Uranium ore in non-Ontario mine

TOTUMTHS Total months of uranium dust exposure

TOTMTHS Total months of dust exposure

GLDB4UR Total months of gold dust exposure before

uranium

MSPYR Year of qualification as a mill worker



SEX sex

DATEONT Date of first Ontario dust exposure

DATENONT Date of first dust exposure NOT in Ontario

AGE1FST Age at first ONTARIO exposure

YLDSEARC Year of last death search

Third Row

YOFUO Year of first uranium exposure in Ontario



YRFST06 First year of dust exposure in ore (asbestos)

YRLST06 Last year of dust exposure in ore (asbestos)

YRFST11 First year of dust exposure in ore (copper)

YRLST11 Last year of dust exposure in ore (copper)

YRFST01 First year of dust exposure in ore (gold)

YRLST01 Last year of dust exposure in ore (gold)

YRFST04 First year of dust exposure in ore (iron)

YRLST04 Last year of dust exposure in ore (iron)

YRFST26 First year of dust exposure in ore (nickel)

Fourth Row

YRLST26 Last year of dust exposure in ore (nickel)



YRFST02 First year of dust exposure in ore

(nickel/copper)

Fifth Row

YRLST02 Last year of dust exposure in ore

(nickel/copper)

210

Record Sequence

Variable Name

Description

YRFST33 First year of dust exposure in ore (quartz)

YRLST33 Last year of dust exposure in ore (quartz)

YRFST03 First year of dust exposure in ore (silver)

YRLST03 Last year of dust exposure in ore (silver)

YRFST42 First year of dust exposure in ore (thorium)

YRLST42 Last year of dust exposure in ore (thorium)

YRFST20 First year of dust exposure in ore (tin)

YRLST20 Last year of dust exposure in ore (tin)



NREC Number of employment records for miner

YRS Year of start of employment sequence

MOS Month and day of start of employment

sequence

WLMS Radiation exposure in WLMs

EMOS Elapse time in months for radiation exposure

MINECD Mine code

OREO Ore code

OCCUPO Occupation code

WCFO Work class factor

WHFO Work history factor

WLSTO Work level standard

Sixth Row

WLSPO Working level special

211

Appendix II: National Dose Registry

The National Dose Registry (NDR) collects and collates exposure data for all

workers in Canada potentially exposed to ionizing radiation. Uranium miners are

among the group of workers monitored by the NDR. For this study, any miners

with a history of uranium mining in Ontario were extracted for analysis. Two

separate files were received from the NDR: 1) Cohort file and 2) Exposure File.

The Cohort File of the NDR contained personal information of the miners such as names, sex, date of birth, place of birth. The Exposure File of the NDR contained information on work history information.

Data File Variable Name Description

Surname Surname

Given_nme_1 First given name

Given_nme_2 Second given name

Sex The sex of an individual

DOB Date of birth

Cohort File

Bplace Place of Birth

EXPOSURE_YEAR Exposure year

FREQUENC Frequency of monitoring

MAXJC Job code

EXTREMIT Parts of body radiated

PROVINCE Province where the dose occurred

GROUP_CL Industry group

SERVICE Service type

SERIAL_N Serial number corresponding to an

organization

JOB_CLAS Code for job classification

BODY_DOS For whole-body gamma/beta exposures

(EXT="0") starting 1981 only,

SKIN_DOS For radon dose (Extremity=8)

FROM_PER First period of monitoring.

TO_PERIO Last period of monitoring.

Exposure File

RECORD_C Number of dose records of an individual in a

given year at a given employer

212

Appendix III: SAS Syntax (Person Years, Grouping, and Model) /************************************************** ******************** Person-Years Calculation Adapted from Pearce & Chec koway (1987) and Villeneuve (2006) *************************************************** *************************/ DATA TEMP; *** DEFINE START YR AND LAG OF EXPOSURES; start= 1954; lagyears= 10; *** TABULATE PYs; *** PART 1 - ALIVE FOLLOW-UP; type= 0; *** NUMBER OF FOLLOW_UP YEARS; follow=(yrout-yrin+ 1); array cum_dose(yr_indx) wlm54-wlm104; RETAIN DUR ; RETAIN CD_LAG1; IF FIRST.newndrlinkid THEN DO;DUR=0;cd_lag1= 0; END; DO YR=1 TO FOLLOW; DOSE= 1;CD=0; if yr= 1 then cd_lag1= 0; yr_indx=floor(yrin+yr-start)-lagyears; if yr_indx< 1 then do; cd= 0;dur= 0; durcat= 1; end ; if yr_indx> 0 then do; if cum_dose= . then do;dose= 1;cd= 0; end ; if cum_dose= 0 then do; dose= 1;cd=cum_dose; end ; if 0<cum_dose<= 0 then do;dose= 1;cd=cum_dose; end ; if 0<cum_dose<= 20.00 then do;dose= 2;cd=cum_dose; end ; if 20.00<cum_dose<= 40 then do;dose= 3;cd=cum_dose; end ; if 40<cum_dose then do;dose= 4;cd=cum_dose; end ; if yr= 1 then do; if cd> 0 then dur= 1; if cd= 0 then dur= 0; end ; if yr> 1 then do; if cd-cd_lag1> 0 then dur=dur+ 1; end ; if 0<=dur< 1 then durcat= 1; if 1<=dur< 2 then durcat= 2; if 2<=dur< 5 then durcat= 3; if 5<=dur then durcat= 4; cd_lag1=cd; end ;

/* Age*/ age = yin-yob; year=yrin+yr- 1; agerisk=year-yob; /* Age at First Employment*/ if age < 25 then agefirst= 1; If 25 <= age < 35 then agefirst = 2; if 35 <= age < 45 then agefirst= 3; if age >= 45 then agefirst= 4; /* Years since exposure*/ if yrs_since < 10 then ryrs_since = 1; If 10 <= yrs_since < 20 then ryrs_since = 2; if 20 <= yrs_since < 30 then ryrs_since = 3;

213

if yrs_since >= 30 then ryrs_since = 4; /* Year of First Employment*/ if yrin < 1957 then yrfirst= 1; If 1957 <= yrin < 1958 then yrfirst = 2; if 1958 <= yrin < 1959 then yrfirst= 3; if yrin >= 1959 then yrfirst= 4; /*--CREATE ATTAINED AGE CATEGORIES --------*/ if agerisk< 60 then attage= 1; if 60<=agerisk< 65 then attage= 2; if 65<=agerisk< 70 then attage= 3; if agerisk>= 70 then attage= 4; /*-- CREATE PERIOD CATEGORIES ----------*/ if year< 1975 then period= 1; if 1975<=year< 1985 then period= 2; if 1985<=year< 1995 then period= 3; if 1995<=year< 2004 then period= 4; if period= '.' then period= 4; IF YR=FOLLOW THEN DO; IF LUNG=1 THEN TYPE=1; IF LUNG=0 THEN TYPE=0; END; IF YR<FOLLOW THEN DO; TYPE= 0; END; OUTPUT TEMP; END; RUN; /* Calculate Mean dose of Quartiles */ Data tempdose1; set temp; if Dose = 1; run; proc univariate data =tempdose1; var cd; run; Data tempdose2; set temp; if Dose = 2; run; proc univariate; var cd; run; Data tempdose3; set temp; if Dose = 3; run; proc univariate; var cd; run; Data tempdose4; set temp; if Dose = 4; run; proc univariate; var cd; run; /* Crosstabulation */ data temp2; set temp; PROC FREQ DATA=temp2; TABLES TYPE*DOSE*ATTAGE*PERIOD*ryrs_since*agefirst*yrfirst / OUT=r6 SPARSE NOPRINT; run; ***EXTRACT THE PYs FROM THE CROSSTABS; data t1;

214

set r6; if type= 0; if period > 0; py1=count; proc sort; by dose attage period ryrs_since; run; ***EXTRACT THE DEATHS FROM THE CROSSTABS; data t2; set r6; if type= 1; if period > 0; deaths=count;py2=count; proc sort; by dose attage period ryrs_since; proc means sum; var count deaths; run; data t3; merge t1 t2; by dose attage period ryrs_since; age2 = attage; /* Mean doses to test for trend*/ If dose= 1 then M_dose= 0; If dose= 2 then M_dose= 5.63; If dose= 3 then M_dose= 28.40; If dose= 4 then M_dose= 94.43;

run; data t4; set t3; py=py1 +py2; drop count percent type py1 py2; if py> 0; lnpyr=log(py); run; proc sort; by dose; proc means sum; var deaths py; by dose; run; Title1 'Esophagus 10 lag incidence' ; proc genmod data =t4; class dose attage period ; model deaths= dose attage period / link =log dist =poisson offset =lnpyr type3 ; estimate 'Dose 2vs1' dose - 1 1 0 0/ exp ; estimate 'Dose 3vs1' dose - 1 0 1 0/ exp ; estimate 'Dose 4vs1' dose - 1 0 0 1/ exp ; run; Title1 'Esophagus 10 lag incidence - Test for Trend' ; /* Calculating linear trend using Paul´s method*/ Proc genmod; class attage period; Model deaths= M_dose attage period / link =log dist =poisson offset =lnpyr; run;

215

Appendix IV: Sample Data for Miner John Doe M ine r y o b y rin yr o ut C D D O S E C a t ( 4 ) a ge _ f irs t a ge r is k a t tag e C a t ( 4 ) ye a r_ r isk p er iod C a t (4 )

S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 6 .2 5 2 2 8 2 8 1 19 6 0 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 6 .8 8 2 2 8 2 9 1 19 6 1 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 .3 5 2 2 8 3 0 1 19 6 2 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 4 0 .6 2 4 2 8 3 1 1 19 6 3 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 7 4 .7 2 4 2 8 3 2 1 19 6 4 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 3 3 1 19 6 5 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 3 4 1 19 6 6 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 3 5 1 19 6 7 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 3 6 1 19 6 8 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 3 7 1 19 6 9 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 3 8 1 19 7 0 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 3 9 1 19 7 1 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 4 0 1 19 7 2 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 4 1 1 19 7 3 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 4 2 1 19 7 4 1S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 4 3 1 19 7 5 2S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 4 4 1 19 7 6 2S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 4 5 1 19 7 7 2S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 4 6 1 19 7 8 2S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 4 7 1 19 7 9 2S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 4 8 1 19 8 0 2S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 4 9 1 19 8 1 2S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 5 0 1 19 8 2 2S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 5 1 1 19 8 3 2S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 5 2 1 19 8 4 2S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 5 3 1 19 8 5 3S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 5 4 1 19 8 6 3S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 5 5 1 19 8 7 3S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 5 6 1 19 8 8 3S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 5 7 1 19 8 9 3S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 5 8 1 19 9 0 3S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 5 9 1 19 9 1 3S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 6 0 2 19 9 2 3S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 6 1 2 19 9 3 3S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 6 2 2 19 9 4 3S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 6 3 2 19 9 5 4S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 6 4 2 19 9 6 4S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 6 5 3 19 9 7 4S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 6 6 3 19 9 8 4S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 6 7 3 19 9 9 4S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 6 8 3 20 0 0 4S J o hn D o e 1 93 2 1 9 6 0 2 0 0 1 8 9 .4 2 4 2 8 6 9 3 20 0 1 4

L e ge n dy o b Y e a r o f b ir thy r in Y e a r o f e n tryy ro ut Y e a r o f e x it ( d iag n o s is /d e ath /e nd o f fo llo w -u p )C D C u m u la t iv e d o s eD O S E C a t ( 4) D e r iv e d v a r ia ble b a s e d o n c u m u lat iv e d o s e ( 4 c a teg o r ies )a g e _ firs t - D e r iv e d f ie ld b a s ed o n ye a r o f b ir th a n d ye a r o f e n trya tta g e C a t ( 4 ) D e r iv e d v a r ia ble b a s e d o n a ge a t ris k ( 4 c a te g or ie s )y e a r_ r is k Y e a r a t r is kP e rio d D e r iv e d v a r ia ble b a s e d o n ye a r a t r is k ( 4 c a teg o r ie s )

216

Appendix V: Sensitivity Analysis I – Lagging

No Lagging applied


0 2 80,291 - 3 81,583 -> 0 - 20 18 648,666 1,23 (0,28-5,29) 21 655,830 1,00 (0,30-3,38)> 20 - 40 9 105,475 3,14 (0,67-14,6) 9 107,413 1,92 (0,52-7,11)


0 3 80,291 - 3 81,583 -> 0 - 20 49 648,666 2,37 (0,73-7,62) 39 655,830 1,96 (0,61-6,35)> 20 - 40 13 105,475 2,72 (0,78-9,55) 10 107,413 2,06 (0,57-7,48)


0 40 80,291 - 17 81,583 -> 0 - 20 198 648,666 0,66 (0,47-0,93) 93 655,830 0,78 (0,47-1,32)> 20 - 40 50 105,475 0,88 (0,58-1,34) 23 107,413 0,87 (0,47-1,63)

> 40 71 126,778 0,95 (0,65-1,41) 43 129,861 1,19 (0,67-2,10)

Total 359 961,210 P trend = 0.04 176 974,687 P trend = 0.04

0 45 80,291 - 23 81,583 -> 0 - 20 265 648,666 0,80 (0,58-1,10) 153 655,830 0,97 (0,62-1,50)> 20 - 40 72 105,475 1,10 (0,76-1,59) 42 107,413 1,16 (0,69-1,93)


0 55 80,291 - 52 81,583 -> 0 - 20 399 648,666 0,99 (0,74-1,31) 344 655,830 0,92 (0,67-1,34)> 20 - 40 116 105,475 1,43 (1,04-1,98) 96 107,413 1,22 (0,87-1,72)


Cancer Site

(ICD-9)



Lung

(162

)

Notes:* - Adjusted for attained age and period; WLM – Working Level Month, RR - Relative Risk; CI-Confidence Interval; and, ICD-9-International Classification of Diseases, 9th Revision; GI - Gastrointestinal Cancer (ICD-9: 150, 151, 153, 154, 159.0); and PY- Person Years;

Eso

phag

us

(150

)

Sto

mac

h

(151

)

Colo

rect

al

(153

, 154

,

159.

0)

Gas

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217

218

Five year lag applied


0 2 208,268 - 4 209,672 -> 0 - 20 18 551,736 1,81 (0,41-7,96) 20 558,805 1,04 (0,34-3,10)> 20 - 40 9 91,391 4,51 (0,95-21,4) 9 93,319 2,01 (0,61-6,70)


0 5 208,268 - 5 209,672 -> 0 - 20 48 551,736 2,84 (1,11-7,24) 38 558,805 2,20 (0,85-5,71)> 20 - 40 13 91,391 3,19 (1,12-9,11) 10 93,319 2,29 (0,76-6,85)


0 47 208,268 - 18 209,672 -> 0 - 20 193 551,736 0,92 (0,66-1,27) 92 558,805 1,14 (0,68-1,91)> 20 - 40 48 91,391 1,15 (0,77-1,75) 23 93,319 1,24 (0,66-2,33)


0 54 208,268 - 27 209,672 -> 0 - 20 259 551,736 1,13 (0,83-1,53) 150 558,805 1,32 (0,86-2,01)> 20 - 40 70 91,391 1,49 (1,03-2,14) 42 93,319 1,57 (0,95-2,57)


0 60 208,268 - 56 209,672 -> 0 - 20 396 551,736 1,74 (1,32-2,29) 342 558,805 1,52 (1,14-2,03)> 20 - 40 116 91,391 2,43 (1,77-3,33) 97 93,319 1,98 (1,42-2,77)


Cancer Site

(ICD-9)


Incidence (1964-2004) Mortality (1954-2004)Lung

(162

)


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(1

50)

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159.

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219

15 year lag applied


0 2 461,533 - 4 463,784 -> 0 - 20 19 359,141 4,25 (0,86-21,0) 20 365,539 2,07 (0,63-6,65)> 20 - 40 8 63,623 8,72 (1,60-47,3) 10 65,564 4,17 (1,18-14,78)


0 18 461,533 - 15 463,784 -> 0 - 20 39 359,141 1,68 (0,85-3,31) 31 365,539 1,49 (0,70-3,20)> 20 - 40 13 63,623 2,13 (0,94-4,83) 9 65,564 1,61 (0,62-4,14)


0 79 461,533 - 31 463,784 -> 0 - 20 172 359,141 1,15 (0,85-1,55) 85 365,539 1,25 (0,77-2,02)> 20 - 40 46 63,623 1,41 (0,95-2,10) 20 65,564 1,22 (0,66-2,26)

> 40 62 76,913 1,42 (0,98-2,06) 40 79,800 1,78 (1,04-3,05)

Total 359 961,210 P trend = 0.08 176 974,687 P trend = 0.03

0 99 461,533 - 50 463,784 -> 0 - 20 230 359,141 1,31 (1,00-1,72) 136 365,539 1,40 (0,95-2,05)> 20 - 40 67 63,623 1,69 (1,20-2,38) 39 65,564 1,61 (1,00-2,57)


0 126 461,533 - 106 463,784 -> 0 - 20 369 359,141 2,20 (1,74-2,78) 316 365,539 2,07 (1,60-2,68)> 20 - 40 114 63,623 2,92 (2,21-3,88) 100 65,564 2,76 (2,03-3,74)


Cancer Site

(ICD-9)



Lung

(162

)


Eso

phag

us

(150

)

Sto

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h

(151

)

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rect

al

(153

, 154

,

159.

0)

Gas

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220

20 year lag applied


0 3 583,373 - 6 586,583 -> 0 - 20 18 265,104 5,27 (1,16-24,0) 19 270,855 2,04 (0,70-5,91)> 20 - 40 8 51,326 11,1 (2,18-55,4) 9 53,198 3,78 (1,16-12,27)


0 26 583,373 - 22 586,583 -> 0 - 20 34 265,104 1,53 (0,78-3,01) 27 270,855 1,26 (0,59-2,67)> 20 - 40 11 51,326 1,81 (0,78-4,19) 7 53,198 1,16 (0,43-3,14)


0 105 583,373 - 42 586,583 -> 0 - 20 155 265,104 1,22 (0,91-1,64) 77 270,855 1,23 (0,77-1,94)> 20 - 40 47 51,326 1,58 (1,08-2,32) 22 53,198 1,38 (0,77-2,49)


0 134 583,373 - 70 586,583 -> 0 - 20 207 265,104 1,35 (1,04-1,76) 123 270,855 1,32 (0,91-1,90)> 20 - 40 66 51,326 1,80 (1,29-2,51) 38 53,198 1,56 (0,99-2,47)


0 210 583,373 - 172 586,583 -> 0 - 20 343 265,104 1,82 (1,47-2,25) 293 270,855 1,72 (1,36-2,18)> 20 - 40 92 51,326 1,97 (1,49-2,60) 85 53,198 1,97 (1,46-2,66)


Cancer Site

(ICD-9)


Incidence (1964-2004) Mortality (1954-2004)Lung

(162

)


Eso

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50)

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221

Appendix VI: Sensitivity Analysis II – Excluding Miners with a history of Gold mining (miner who start after 1986 when the WHF ended was assumed to be non-gold miners)


0 0 187,005 - 2 187,692 -> 0 - 20 11 279,936 Non-est 13 283,723 1,46 (0,30-7,08)> 20 - 40 5 40,503 Non-est 4 41,404 2,27 (0,38-13,57)

> 40 2 46,642 Non-est 3 48,095 1,28 (0,20-8,35)Total 18 554,086 P trend = NA 22 560,914 P trend = 0.96

0 6 187,005 - 4 187,692 -> 0 - 20 24 279,936 1,53 (0,57-4,14) 17 283,723 1,78 (0,52-6,05)> 20 - 40 4 40,503 1,25 (0,32-4,78) 4 41,404 1,96 (0,43-8,78)


0 29 187,005 - 13 187,692 -> 0 - 20 98 279,936 1,03 (0,65-1,63) 41 283,723 0,83 (0,41-1,66)> 20 - 40 23 40,503 1,36 (0,76-2,43) 9 41,404 0,89 (0,36-2,21)


0 35 187,005 - 19 187,692 -> 0 - 20 133 279,936 1,18 (0,78-1,78) 71 283,723 1,08 (0,61-1,89)> 20 - 40 32 40,503 1,56 (0,93-2,61) 17 41,404 1,26 (0,62-2,54)


0 38 187,005 - 31 187,692 -> 0 - 20 184 279,936 1,82 (1,25-2,65) 160 283,723 1,78 (1,17-2,69)> 20 - 40 54 40,503 2,92 (1,89-4,53) 41 41,404 2,40 (1,00-1,87)


Lung

(162

)


Cancer Site

(ICD-9)



Eso

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(150

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Appendix VII: Sensitivity Analysis IV – Pre-1968 (Miners who start employment prior to 1968)

C ases P Y R R (95% C I)* D eath s P Y R R (95% C I)*

0 2 1 8 0.6 8 7 - 3 1 8 1.3 7 6 -> 0 - 20 1 5 2 5 6.6 4 7 1 ,4 0 (0 ,3 0-6 ,6 1) 1 7 2 6 0.7 9 4 0 ,9 9 (0 ,2 8 -3 ,5 7 )

> 2 0 - 40 9 7 2.4 5 7 2 ,9 3 (0 ,5 9-1 4 ,7) 9 7 4.2 8 0 1 ,7 4 (0 ,4 5 -6 ,7 6 )> 4 0 5 9 2.4 6 3 1 ,2 1 (0 ,2 1-6 ,7 1) 7 9 5.4 6 1 0 ,9 6 (0 ,2 3 -3 ,8 8 )T o tal 3 1 6 0 2.2 5 4 P t re n d = 0 .8 6 3 6 6 1 1.9 1 1 P tre nd = 0.9 1

0 6 1 8 0.6 8 7 - 6 1 8 1.3 7 6 -> 0 - 20 3 5 2 5 6.6 4 7 2 ,3 7 (0 ,9 2-6 ,1 1) 2 9 2 6 0.7 9 4 1 ,9 8 (0 ,7 5 -5 ,2 4 )

> 2 0 - 40 1 4 7 2.4 5 7 3 ,1 4 (1 ,1 2-8 ,8 4) 1 0 7 4.2 8 0 2 ,2 3 (0 ,7 4 -6 ,6 9 )> 4 0 1 8 9 2.4 6 3 2 ,8 4 (1 ,0 3-7 ,8 4) 1 5 9 5.4 6 1 2 ,3 2 (0 ,8 1 -6 ,6 1 )T o tal 7 3 6 0 2.2 5 4 P t re n d = 0 .2 5 6 0 6 1 1.9 1 1 P tre nd = 0.3 6

0 2 7 1 8 0.6 8 7 - 1 7 1 8 1.3 7 6 -> 0 - 20 1 1 4 2 5 6.6 4 7 0 ,9 7 (0 ,6 1-1 ,5 3) 6 7 2 6 0.7 9 4 0 ,9 4 (0 ,5 2 -1 ,6 9 )

> 2 0 - 40 4 6 7 2.4 5 7 1 ,3 3 (0 ,8 0-2 ,2 2) 1 8 7 4.2 8 0 0 ,8 4 (0 ,4 1 -1 ,7 0 )> 4 0 6 8 9 2.4 6 3 1 ,4 1 (0 ,8 7-2 ,3 0) 4 2 9 5.4 6 1 1 ,3 8 (0 ,7 4 -2 ,5 7 )

T o tal 2 5 5 6 0 2.2 5 4 P t re n d = 0 .0 1 1 4 4 6 1 1.9 1 1 P tre nd = 0.0 5

0 3 5 1 8 0.6 8 7 - 2 6 1 8 1.3 7 6 -> 0 - 20 1 6 4 2 5 6.6 4 7 1 ,2 1 (0 ,8 1-1 ,8 2) 1 1 3 2 6 0.7 9 4 1 ,1 6 (0 ,7 2 -1 ,8 6 )

> 2 0 - 40 6 9 7 2.4 5 7 1 ,7 3 (1 ,1 1-2 ,6 9) 3 7 7 4.2 8 0 1 ,2 6 (0 ,7 3 -2 ,1 6 )> 4 0 9 1 9 2.4 6 3 1 ,6 4 (1 ,0 6-2 ,5 1) 6 4 9 5.4 6 1 1 ,5 3 (0 ,9 2 -2 ,5 2 )T o tal 3 5 9 6 0 2.2 5 4 P tr e n d = 0 . 2 4 0 6 1 1.9 1 1 P tre nd = 0.0 5

0 3 8 1 8 0.6 8 7 - 4 3 1 8 1.3 7 6 -> 0 - 20 2 8 8 2 5 6.6 4 7 2 ,4 5 (1 ,7 1-3 ,5 4) 2 5 0 2 6 0.7 9 4 1 ,7 8 (1 ,2 5 -2 ,5 4 )

> 2 0 - 40 1 1 0 7 2.4 5 7 3 ,1 9 (2 ,1 5-4 ,7 3) 9 4 7 4.2 8 0 2 ,2 4 (1 ,5 2 -3 ,3 1 )> 4 0 2 6 1 9 2.4 6 3 5 ,4 6 (3 ,7 7-7 ,9 1) 2 2 8 9 5.4 6 1 3 ,8 9 (2 ,7 1 -5 ,5 7 )

T o tal 6 9 7 6 0 2.2 5 4 P t re n d < 0 .0 1 6 1 5 6 1 1.9 1 1 P tre nd < 0.0 1

Lu

ng

(162

)

N ote s :* - A djus te d fo r a tta in ed a g e a n d pe r io d ; W L M – W o rk in g L eve l M o nth , R R - R e la ti ve R isk ; C I-C on fid e n ce In te rva l; a n d , IC D -9 -In te rna tio n al C las s ifica tion o f D ise a se s , 9th R e v is io n ; G I - G a s troin te s tin a l C an ce r ( IC D -9 : 1 5 0, 1 5 1 , 1 5 3 , 15 4 , 1 59 .0 ) ; a n d P Y - P e rso n Y ea rs ;

Ca nce r Si te

(ICD -9 )

Cu mu la tive Ra do n D o se ( W L M )

In c ide n c e (1 9 64 -2 0 04 ) M o rta lity (1 9 5 4 -2 0 0 4 )

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223

Appendix VIII: Ungrouped Poisson Regression Model and Statistical Test of

Interaction

Although Poisson regression using grouped data is a well accepted

approach to model disease as a function of covariates in occupational

epidemiology [1, 2] a more recent paper published by Loomis and colleagues

[3] indicates that it might be more beneficial to use ungrouped data. Arguments

presented for ungrouped data include better statistical power and avoiding the

need to categorize data that was originally measured on a continuous scale [3].

Furthermore, Loomis and colleagues [3]also suggest that ungrouped data is

preferred when looking at interactions of covariates especially those that are

subject to change over time (i.e., time dependent covariates). Given that the

current thesis used grouped data and examined effect modification through

stratification, the Loomis publication provides the basis to re-examine study

results using ungrouped data and formal examination interactions using

modelling approaches [3].

Data Preparation

The initial data preparation stage for grouped and ungrouped data

analysis is the same. Both approaches start with identifying cohort members and

followed until an event of interest or end of follow-up, which ever occurred first.

An analytical data set is constructed for each unit of person-time at risk. For

grouped data analysis, person-data are then cross classified. In this thesis,

cumulative dose, age at risk (attained age), and period at risk are cross

classified into four categories. Cumulative doses are grouped into 20 WLM

(referent group = 0 WLM) increments for ease of interpretation of dose response

relationships. An example of the continuous and of cross-classified data for

miner ‘John Doe’ is shown in appendix IV of this thesis.

224

Data Analysis

SAS procedure ‘PROC GENMOD’ is used to derive risk estimates for both

grouped and ungrouped data. However, in grouped data, an offset (person-

years) is used to account for the duration of follow-up. In ungrouped data, all

observations contribute equal weight and therefore, the offset term need not

be specified when fitting the Poisson regression model to ungrouped data. As

such, the ungrouped approach assumes that each person-year is independent

of another for the same person.

In this analysis, effect modification by duration of employment on the

association between cumulative exposure to radon decay products (WLM) and

cancer deaths is examined. Two cancer sites were selected (colorectal and

lung cancer deaths) due to large number of cases. Although effect modifiers

can be determined through stratification, in this section formal statistical

methods are used to test for the interaction of the product term.

Log (λ) = β0 + β1 (AGE) + β2 (YEAR) + β3 (WLM) + β4 (DUR) + β5 (WLM*DUR)

Where λ is estimated by the ratio of observed events and corresponding sum of

follow-up, βs are coefficient for continuous covariates age (AGE), year of

exposure (YEAR), radon (WLM), duration of employment (DUR) and the

interaction tem between exposures and duration (WLM*DUR).

Model Fit

For each model, a deviance statistics was computed. The deviance

provides an absolute measure of the measure of the residual (unexplained)

variation [2]. The deviance has an approximate chi-square distribution with n-p

degrees of freedom (DF) where n represent the number of observations and p is

the number of predictor variables. When a model fits the data well, the ratio of

the deviance to DF approximates 1. A ratio above 1 indicates over-dispersion

while one less than 1 indicates under-dispersion.

225

Results

For both colorectal and lung cancer deaths, age at risk is positively

related to cancer deaths while year at risk is inversely related to cancer risks

(lower risk for more recent years).

Model 1 of Tables 1 and 2 show the effects of cumulative doses on

colorectal and lung cancer mortality risks respectively. In both instances, they

are positively associated with cumulative doses of radon decay products.

However, the effects are approximately 3 times higher for lung cancer (β=

0.0043) than colorectal cancer (β =0.0016). This is expected given that radiation

dosimetry indicates that most of the doses from radon decay products are to

the lungs rather than the colorectal area. Model 2 of Tables 1 and 2 show the

effects of duration of employment on colorectal and lung cancer mortality risks

respectively. Duration of exposure is also an important factor in both colorectal

(β= 0.0547) and lung cancer (β= 0.0932) deaths. Model 3 of Tables 1 and 2 shows

the effects of the interaction between cumulative doses and duration of

employment on colorectal and lung cancer risks respectively. In both instances,

the beta coefficients of the main effects indicate that as dose and duration of

employment increases, the risk of both colorectal and lung cancer also

increases. However, as dose and duration increases, the risk decreases as

confirmed by a small but statistically significant (p < 0.01) interaction term

between dose and duration of exposure. These observations confirm results of

stratified grouped analyses shown in Tables 14 and 15 for incidence and

mortality respectively.

226

Table 1: Estimated regression beta coefficients, standard errors, and model fit

statistics for colorectal cancer deaths associated with cumulative radon decay

products exposure (10-year lag) and duration of employment for Ontario

uranium miners.

Model

Model 1: Age, Year, Radon (WLM) β (SE) P-value Deviance/DF

Age at risk (Age) 0,0503 (0,0012) <0,0001 0,0562

Year at risk (Year) -0,0731 (0,0013) <0,0001

Cumulative Radon (WLM) 0,0016 (0,0003) <0,0001

Model 2: Age, Year, Duration

Age at risk (Age) 0,0498 (0,0012) <0,0001 0,0561

Year at risk (Year) -0,0773 (0,0014) <0,0001

Duration of Employment (DUR) 0,0547 (0,0040) <0,0001

Model 3: Age, Year, Radon (WLM), Duration, Radon (WLM)*Duration

Age at risk (Age) 0,0498 (0,0012) <0,0001 0,0560

Year at risk (Year) -0,0796 (0,0014) <0,0001

Cumulative Radon (WLM) 0,0019 (0,0006) 0,0019


Radon (WLM)*Duration -0,0005 (0,0001) <0,0001

Note: SE- Standard error, DF- degrees of freedom, WLM-radon decay products measured in Working Level Months

Colorectal Cancer (1954-2004)

227

Table 2: Estimated regression beta coefficients, standard errors, and model fit

statistics for lung cancer deaths associated with cumulative radon decay

products exposure (10-year lag) and duration of employment for Ontario

uranium miners.

Model

Model 1: Age, Year, Radon (WLM) β (SE) P-value Deviance/DF

Age at risk (Age) 0,0466 (0,0006) <0,0001 0,1565

Year at risk (Year) -0,0786 (0,0007) <0,0001


Model 2: Age, Year, Duration

Age at risk (Age) 0,0466 (0,0006) <0,0001 0,1556

Year at risk (Year) -0,0866 (0,0007) <0,0001


Model 3: Age, Year, Radon (WLM), Duration, Radon (WLM)*Duration

Age at risk (Age) 0,0452 (0,0006) <0,0001 0,1553

Year at risk (Year) -0,0856 (0,0007) <0,0001



Radon (WLM)*Duration -0,0001 (0,0000) 0,0002

Note: SE- Standard error, DF- degrees of freedom, WLM-radon decay products measured in Working Level Months

Lung Cancer (1954-2004)

References:

1. Breslow, N.E. and N.E. Day, Statistical Methods in Cancer Research,

Volume II - The Design and Analysis of Cohort Studies, ed. I.A.R.C. 1987.

p.3.

2. Frome, E.L. and H. Checkoway, Epidemiologic programs for computers

and calculators. Use of Poisson regression models in estimating incidence

rates and ratios. Am J Epidemiol, 1985. 121(2): p. 309-23.

3. Loomis, D., D.B. Richardson, and L. Elliott, Poisson regression analysis of

ungrouped data. Occup Environ Med, 2005. 62(5): p. 325-9.

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